TRAINING MATERIALS
FOR EXAMINING PATENT APPLICATIONS WITH RESPECT TO 35 U.S.C. SECTION
112, FIRST PARAGRAPH-ENABLEMENT OF CHEMICAL/BIOTECHNICAL APPLICATIONS
TABLE OF CONTENTS
- I.LEGAL JUSTIFICATION
- A.CONSTITUTIONAL AUTHORITY
- B.STATUTORY MANDATES
- II. OVERVIEW OF EXAMINATION
- A. PROCEDURAL
- B. ASSUMPTIONS/ BURDEN ON THE EXAMINER
- III. DETERMINING WHETHER THE ENABLEMENT REQUIREMENT
IS MET
- A. NECESSARY FACTORS TO EVALUATE
- Scope/ Breadth of the Claims
- Reasons For Lack Of Enablement: Undue
Experimentation Needed To Make And Use The Invention
- B. UTILITY AND OPERABILITY
- Preferred Materials in Specification Need
not be in the Claims
- Inoperability/Inoperative Species within
the Scope of the Claim
- C. LACK OF ENABLEMENT IN VIEW OF AN OBVIOUSNESS
REJECTION
- D. THE INVENTION MAY BE ENABLED BUT NOT
ADEQUATELY DESCRIBED
- IV. COMMUNICATING FINDINGS TO THE APPLICANT
- A. THE LEVEL OF DETAIL
- B. THE FORM PARAGRAPHS
- 35 U.S.C. 112,1st, Enablement 7.31.02
- 35 U.S.C. 112, 1st, Scope Of Enablement
7.31.03
- 35 U.S.C. 112, 1st, Essential Subject
Matter Missing From Claims (Enablement) , 7.33.01
:
- Multiple Use of Form Paragraphs
- Practical Tips in Writing the Rejection
- V. REBUTTAL TO THE REJECT5ION PROOF OF ENABLEMENT
- EVIDENCE AND ATTORNEY ARGUMENT
- A. USE OF POST FILING DATE EVIDENCE
- B. EXPERT DECLARATIONS
- C. USE OF FDA SUBMISSIONS
- ENABLEMENT DECISION TREE
- Example A: Hybridization Probes I
- Example B: Hybridization Probes II
- Example C: Chemical Reagents I
- Example D: Chemical Reagents II
- Example E: Peptides for Treating Obesity
- Example F: Enablement and Prior Art Rejections
- Example G: Gene Therapy
- Example H: Endothelin Receptor Antagonists
- Example I: Transgenic Animals
- Example J: Selectin-Mediated Cellular Adhesion
- Example K: HIV
- Example L: Alzheimer's Disease
- Example M: Polymers
- Example N: DNA
- Example O: Vaccines
REFERENCE LIST
TRAINING MATERIALS FOR EXAMINING PATENT APPLICATIONS
WITH RESPECT TO 35 U.S.C. SECTION 112, FIRST PARAGRAPH-ENABLEMENT
CHEMICAL/BIOTECHNICAL APPLICATIONS
I. LEGAL JUSTIFICATION
A. CONSTITUTIONAL AUTHORITY
Requiring an applicant to provide information about the invention
in his patent application to enable any person skilled in
the art to make and use the invention is just one aspect of the "quid
pro quo" for obtaining the legal right to exclude others from making,
using, selling, offering for sale, or importing the claimed invention.
The right to exclude others is the personal property right of the
patent owner and is not granted by the government without the public
obtaining a public good, i.e., the promotion of the progress of
science and the useful arts. The founding fathers of the United
States of America recognized the public good that would flow from
the promotion of science and the useful arts and specifically granted
Congress the authority to establish a patent system.
Authority for Congress to establish the United States patent system
is based in the United States Constitution which provides in pertinent
part:
The Congress shall have Power . . . to promote the Progress
of Science and Useful arts, by securing for a limited Time to Authors
and Inventors the exclusive Right to their respective Writings
and Discoveries . . . .
Article I, Section 8.
With this constitutional authority, Congress enacted Title 35
of the United States Code establishing the patent laws for the
United States of America. Simply granting patents does not necessarily
promote science and the useful arts. Rather, promotion of the progress
of science and the useful arts is achieved by granting a patent
in exchange for the public disclosure of the invention. Thus, Congress
required more than a mere disclosure of the invention; Congress
also required the inventor to teach the public how to make and
use the invention as well. This requirement ensures that the invention
will be available to the public once the patent term expires.
B. STATUTORY MANDATES
The requirement that the inventor adequately disclose his invention
to obtain the right to exclude others from making, using, selling,
offering for sale, or importing the claimed invention is mandated
by 35 U.S.C. Section 112.
Section 112, first paragraph, provides:
The specification shall contain a written description
of the invention, and of the manner and process of making
and using it, in such full, clear, concise, and exact terms
as to enable any person skilled in the art to which it pertains,
or with which it is most nearly connected, to make and use
the same, and shall set forth the best mode contemplated
by the inventor of carrying out his invention. (Emphasis added.)
The emphasized terms are the three requirements from Section 112,
first paragraph, that the patent specification must meet in order
to be a valid patent. An "enabling" disclosure is only one of the
three requirements for the specification.
In addition to being an "enabling" disclosure, the specification
must also provide an adequate "written description" of the invention
and must disclose the embodiment of the invention that the inventor
believes to be the "best mode" of the invention. The written description
and best mode requirements are separate and distinct from the enablement
requirement. Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1563,
19 USPQ2d 1111, 1116-17 (Fed. Cir. 1991); and MPEP Section 2161.
A working definition for the written description and best mode
requirements are provided below only to assist in distinguishing
these additional specification requirements from the enablement
requirement.
The "written description" requirement requires the inventor to
clearly convey to those skilled in the art through the specification
the information that the applicant has invented as the specific
subject matter of the claims. In re Wertheim, 541 F.2d 257,
262, 191 USPQ 90, 96 (CCPA 1976). Although the applicant does not
have to describe the subject matter claimed in the specification
using exactly the same words used in the claims, the description
must be sufficiently clear to allow one of ordinary skill to recognize
that the applicant invented what is claimed. In re Lukach,
442 F.2d 967, 969, 169 USPQ 795, 796 (CCPA 1971); In re Gosteli,
872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989).
The "best mode" requirement mandates that the applicant disclose
in the specification the "best mode" or the best way known to the
inventor at the time of filing the application for carrying out
the invention. Even though disclosing the best mode is a statutory
requirement, it is unlikely that an examiner would ever have sufficient
evidence to raise any doubt about whether the best mode has been
disclosed.
II. OVERVIEW OF EXAMINATION
A. PROCEDURAL
Examination begins with a thorough review of the application in
its entirety and with a preliminary determination of the scope
of the claims. The examiner needs to determine what the claims
recite and determine the meaning of each claim as a whole.
The analysis should be systematic so that no claim is overlooked.
The scope of dependent claims should be determined in addition
to the scope of the independent claims. "A claim in dependent form
shall be construed to incorporate by reference all the limitations
of the claim to which it refers." 35 U.S.C. Section 112, fourth
paragraph.
After the application has been read and the claimed invention
understood, a prior art search for the claimed invention is made.
With the results of the prior art search, including any references
provided by the applicant, the patent application should be reviewed
and analyzed in conjunction with the state of the prior art to
determine whether the claims define a novel, non-obvious, and enabled
invention that has been clearly described in the specification.
The goal of examination is to clearly articulate any rejection
early in the prosecution process so that the applicant has the
opportunity to provide evidence of patentability and otherwise
respond completely at the earliest opportunity. The examiner then
reviews all the evidence, including arguments and evidence responsive
to any rejection before issuing a Notice of Allowance or a final
rejection.
These training materials provide the analytical framework and
a discussion of relevant factors that the examiner should consider
when determining whether there is sufficient evidence to support
a determination that the specification does not enable one skilled
in the art to make and use the claimed invention.
B. ASSUMPTIONS/ BURDEN ON THE EXAMINER
When rejecting a claim under the enablement requirement of section
112, the examiner bears the "initial burden of setting forth a
reasonable explanation as to why [he/she] believes that the scope
of protection provided by [the] claim is not adequately enabled
by the description of the invention provided in the specification." In
re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed.
Cir. 1993). To object to a specification on the grounds that the
disclosure is not enabling with respect to the scope of a claim
sought to be patented, the examiner must provide evidence or technical
reasoning substantiating those doubts. Id.; and MPEP Section
2164.04.
Without a reason to doubt the truth of the statements made in
the patent application, the application must be considered enabling. In
re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed.
Cir. 1993); In re Marzocchi, 439 F.2d 220, 223, 169 USPQ
367, 369 (CCPA 1971). The burden placed on the examiner is reflected
in the MPEP Section 706.03.
Accordingly, the case law makes clear that properly reasoned and
supported statements explaining any failure to comply with Section
112 are a requirement to support a rejection. In re Wright,
999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
III. DETERMINING WHETHER THE ENABLEMENT REQUIREMENT IS MET
In making the determination of enablement, the examiner shall
consider the original disclosure and all evidence in the record,
weighing evidence that supports enablement against the evidence
that the specification is not enabling.
In the mid-1800's the Supreme Court reasoned that a specification
would be defective if it required one with skill to "experiment" in
order practice the claimed invention. Wood v. Under Hill, 46
U.S. (4 How.) 1 (1847). The standard for determining whether
the specification met the enablement requirement was recast in
the later Supreme Court decision of Mineral Separation v. Hyde, 242
U.S. 261, 270 (1916) which postured the question: is the experimentation
needed to practice the invention undue or unreasonable? That standard
is still the one to be applied. In re Wands, 858 F.2d 731,
737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). Accordingly, even though
the statute does not use the term "undue experimentation," it has
been interpreted to require that the claimed invention be enabled
so that any person skilled in art can make and use the invention
without undue experimentation. In re Wands, 858 F.2d 731,
737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
There are many factors to be considered when determining whether
there is sufficient evidence to support a determination that a
disclosure does not satisfy the enablement requirement and whether
any necessary experimentation is "undue." These factors include,
but are not limited to:
- the breadth of the claims,
- the nature of the invention,
- the state of the prior art,
- the level of one of ordinary skill,
- the level of predictability in the art,
- the amount of direction provided by the inventor,
- the existence of working examples, and
- the quantity of experimentation needed to make or use the invention
based on the content of the disclosure. In re Wands, 858
F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988) (reversing
the PTO's determination that claims directed to methods for detection
of hepatitis B surface antigens did not satisfy the enablement
requirement).
In Wands, the court noted that the there was no disagreement
as to the facts, but merely a disagreement as to the interpretation
of the data and the conclusion to be made from the facts. In
re Wands, 858 F.2d at 736-40, 8 USPQ2d at 1403-07. The court
held that the specification was enabling with respect to the claims
at issue and found that "there was considerable direction and guidance" in
the specification; there was "a high level of skill in the art
at the time the application was filed;" and "all of the methods
needed to practice the invention were well known." Id. at
740, 8 USPQ2d at 1406. After considering all the factors related
to the enablement issue, the court concluded that "it would not
require undue experimentation to obtain antibodies needed to practice
the claimed invention." Id., 8 USPQ2d at 1407.
It is improper to conclude that a disclosure is not enabling based
on an analysis of only one of the above factors while ignoring
one or more of the others. The examiner's analysis must consider
all the evidence related to each of these factors, and any conclusion
of non-enablement must be based on the evidence as a whole. Id. at
737 & 740, 8 USPQ2d at 1404 & 1407.
A conclusion of lack of enablement means that, based on the evidence
regarding each of the above factors, the specification, at the
time the application was filed, would not have taught one skilled
in the art how to make and/or use the full scope of the claimed
invention without undue experimentation. In re Wright, 999
F.2d at 1562, 27 USPQ2d at 1513.
The determination that "undue experimentation" would have been
needed to make and use the claimed invention is not a single, simple
factual determination. Rather, it is a conclusion reached by weighing
all the above noted factual considerations. In re Wands, 858
F.2d at 737, 8 USPQ2d at 1404. These factual considerations are
discussed more fully below.
A. NECESSARY FACTORS TO EVALUATE
Before any analysis of enablement can occur, it is necessary for
the examiner to construe the claims. For terms that are not well-known
in the art, or for terms that could have more than one meaning, it
is absolutely necessary that the examiner select the definition that
he/she intends to use when examining the application, based on his/her
understanding of what applicant intends it to mean, and explicitly
set forth the meaning of the term and the scope of the claim when
writing an Office action. See Genentech v. Wellcome Foundation, 29
F.3d 1555, 1563-64, 31 USPQ2d 1161, 1167-68 (Fed. Cir. 1994).
1. Scope/ Breadth of the Claims
Determining whether the enablement requirement has been met requires
analyzing the claim to determine its scope.
All questions of enablement are evaluated against the claimed
subject matter. The focus of the examination inquiry is whether
everything within the scope of the claim is enabled. Accordingly,
the first analytical step requires that the examiner determine
exactly what subject matter is encompassed by the claims. The examiner
should determine what each claim recites and what the subject matter
is when the claim is considered as a whole, not when its
parts are analyzed individually. No claim should be overlooked.
With respect to dependent claims, Section 112, fourth paragraph,
of Title 35 should be followed. This paragraph states that "a claim
in a dependent form shall be construed to incorporate by reference
all the limitations of the claim to which it refers" and requires
the dependent claim to further limit the subject matter claimed.
The Federal Circuit has repeatedly held that "the specification
must teach those skilled in the art how to make and use the full
scope of the claimed invention without 'undue experimentation'." In
re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed.
Cir. 1993). Nevertheless, not everything necessary to practice
the invention need be disclosed. In fact, what is well-known is
best omitted. In re Buchner, 929 F.2d 660, 661, 18 USPQ2d
1331, 1332 (Fed. Cir. 1991). All that is necessary is that one
skilled in the art be able to practice the claimed invention, given
the level of knowledge and skill in the art. Further the scope
of enablement must only bear a "reasonable correlation" to the
scope of the claims. E.g., In re Fisher, 427 F.2d
833, 839, 166 USPQ 18, 24 (CCPA 1970).
In this regard, MPEP Section 2164.08 provides, in pertinent part,
as follows.
As concerns the breadth of a claim relevant to enablement,
the only relevant concern should be whether the scope of enablement
provided to one skilled in the art by the disclosure is commensurate
with the scope of protection sought by the claims. In re Moore,
439 F.2d 1232, 169 USPQ 236 (CCPA 1971)
The determination of the propriety of a rejection based upon
the scope of a claim relative to the scope of the enablement
involves two stages of inquiry. The first is to determine how
broad the claim is with respect to the disclosure. The entire
claim must be considered. The second inquiry is to determine
if one skilled in the art is [sic, would have been] enabled to
make and use the entire scope of the claimed invention without
undue experimentation.
. . .
If a rejection is made based on the view that the enablement
is not commensurate in scope with the claim, the examiner
should identify the subject matter that is considered to be enabled. [Emphasis
added.]
One does not look to the claims but to the specification to find
out how to practice the claimed invention. W.L. Gore & Assoc.,
Inc. v. Garlock, Inc., 721 F.2d 1540, 1558, 220 USPQ 303, 316-17
( Fed. Cir. 1983); In re Johnson, 558 F.2d 1008, 1017, 194
USPQ 187, 195 (CCPA 1977). In In re Goffe, 542 F.2d 564,
567, 191 USPQ 429, 431 (CCPA 1976), the court stated:
to provide effective incentives, claims must adequately
protect inventors. To demand that the first to disclose shall limit
his claims to what he has found will work or to materials which
meet the guidelines specified for "preferred" materials in a process
such as the one herein involved would not serve the constitutional
purpose of promoting progress in the useful arts.
When analyzing the enabled scope of a claim, the teachings of
the specification must not be ignored because claims are to be
given their broadest reasonable interpretation that is consistent
with the specification. "That claims are interpreted in light of
the specification does not mean that everything in the specification
must be read into the claims." Raytheon Co. v. Roper Corp., 724
F.2d 951, 957, 220 USPQ 592, 597 (Fed. Cir. 1983), cert. denied, 469
U.S. 835 (1984).
Part of the examiner's job is to clarify the record so that the
public will have notice as to the patentee's scope of protection
when the patent issues. If a reasonable interpretation of the claim
is broader than the description in the specification, it is necessary
for the examiner to take the additional time and effort to make
sure the full scope of the claim is enabled. Limitations and examples
in the specification do not generally limit what is covered by
the claims. Consequently, if the claim is to a method of transforming
cells and the broadest reasonable interpretation of the claim includes
transforming cells in vivo for gene therapy, the examiner
must make a determination as to whether there is sufficient evidence
to support a conclusion that such scope is not enabled. If applicants
intended only in vitro use, such a limitation should appear
in the claims.
The breadth of the claims was a factor considered in Amgen
v. Chugai Pharm. Co., 927 F.2d 1200, 18 USPQ2d 1016 (Fed.
Cir.), cert. denied, 502 U.S. 856 (1991). In the Amgen case,
the patent claims were directed to a purified DNA sequence encoding
polypeptides which are analogs of erythropoietin (EPO). The court
stated that:
Amgen has not enabled preparation of DNA sequences sufficient
to support its all-encompassing claims. . . . [D]espite extensive
statements in the specification concerning all the analogs of the
EPO gene that can be made, there is little enabling disclosure
of particular analogs and how to make them. Details for preparing
only a few EPO analog genes are disclosed. . . . This disclosure
might well justify a generic claim encompassing these and similar
analogs, but it represents inadequate support for Amgen's desire
to claim all EPO gene analogs. There may be many other genetic
sequences that code for EPO-type products. Amgen has told how to
make and use only a few of them and is therefore not entitled to
claim all of them.
927 F.2d at 1213-14, 18 USPQ2d at 1027.
The court in Amgen focused on the fact that the claims
were directed to DNA sequences that encoded amino acid sequences,
wherein the amino acid sequences had substitutions but preserved
a particular physiological activity. Thus, the amino acid sequences
mentioned in the claims in Amgen were of differing scope.
Additionally, the specification did not give those skilled in the
art guidance as to which amino acids could be changed to either
preserve or enhance the activity of the protein. Because a very
small change in the amino acid sequence of a protein can result
in a very large change in the structure-function activity of a
protein and because the laws of protein folding are in such a primitive
state, predicting protein structure (and hence, activity) while
knowing only the sequence of the protein is akin to predicting
the weather for a date in the distant future.
Similarly, in In re Wright, 999 F.2d 1557, 27 USPQ2d 1510
(Fed. Cir. 1993), the court affirmed the Board's decision and stated
that the evidence did not show that a skilled artisan would have
been able to carry out the steps required to practice the full
scope of claims which encompass "any and all live, non-pathogenic
vaccines, and processes for making such vaccines, which elicit
immunoprotective activity in any animal toward any RNA
virus." 999 F.2d at 1562, 27 USPQ2d at 1513 (original emphasis).
In In re Goodman, 11 F.3d 1046, 1052, 29 USPQ2d 2010, 2015
(Fed. Cir. 1993), the claims were directed to a method for producing
mammalian peptides in plant cells by the integration of a DNA construct
encoding mammalian peptide into plant cells. The court, in affirming
the Board's decision, found that the specification did not support
the broad scope of the claims because the specification contained
only an example of producing gamma-interferon in a dicot species;
and there was evidence that extensive experimentation would have
been required for encoding mammalian peptide into a monocot plant
at the time of filing. Thus, the application would not have enabled
one of skill in the field of biotechnology to produce any type
of mammalian peptide in any plant cell as broadly claimed.
2. Reasons For Lack Of Enablement: Undue Experimentation Needed
To Make And Use The Invention
a. Points of Reference
Whether the specification would have been enabling as of the filing
date involves many of the same considerations that are evaluated
for determining whether or not the claimed invention would have
been obvious as of the date it was invented. These considerations
are: the nature of the invention, the state of the prior art, and
the level of skill in the art. These considerations are reviewed
here briefly in summary form to assist the explanation of the enablement
analysis.
i. Nature of the Invention
The initial inquiry is into the nature of the invention, i.e.,
the subject matter to which the claimed invention pertains. The
nature of the invention becomes the backdrop to determine the state
of the art and the level of skill possessed by one skilled in the
art.
ii. State of the Art
The state of the prior art is what one skilled in the art a would
have known, at the time the application was filed, about the subject
matter to which the claimed invention pertains. The state of the
prior art provides evidence for the degree of predictability in
the art and is related to the amount of direction or guidance needed
in the specification as filed to meet the enablement requirement.
The state of the prior art is also related to the need for working
examples in the specification.
The state of the art for a given technology is not static in time.
It is entirely possible that a disclosure filed on January 2, 1990,
would not have been enabled; however, if the same disclosure had
been filed on January 2, 1996, it might have enabled the claims.
Therefore, the state of the prior art must be evaluated for each
application based on its filing date.
(a) Relevant Art
Section 112 requires the specification to be enabling only to
a person "skilled in the art to which it pertains, or with which
it is most nearly connected." In general, the pertinent art should
be defined in terms of the problem to be solved rather than in
terms of the technology area, industry, trade, etc. for which the
invention is used.
(b) Well-Known Information
The specification need not disclose what is well-known to those
skilled in the art and preferably omits that which is well-known
to those skilled and already available to the public. In re
Buchner, 929 F.2d 660, 661, 18 USPQ2d 1331, 1332 (Fed. Cir.
1991); Hybritech Inc. v. Monoclonal Antibodies, Inc.,
802 F.2d 1367, 1384, 231 USPQ 81, 94 (Fed. Cir. 1986), cert.
denied, 480 U.S. 947 (1987); and Lindemann Maschinenfabrik
GMBH v. American Hoist & Derrick Co., 730 F.2d 1452, 1463,
221 USPQ 481, 489 (Fed. Cir. 1984).
iii. Level of Skill
The relative skill of those in the art refers to the skill of
those in the art in relation to the subject matter to which the
claimed invention pertains at the time the application was filed.
b. Amount of Direction or Guidance Present: Sufficiency of Disclosure
/ Predictability/ Non-Predictability
The "amount of guidance or direction present" refers to that information
in the application, as originally filed, that teaches exactly how
to make or use the invention. The amount of guidance or direction
needed to enable the invention is inversely related to the amount
of knowledge in the state of the art as well as the predictability
in the art. In re Fisher, 427 F.2 833, 839, 166 USPQ 18,
24 (CCPA 1970). The more that is known in the prior art about the
nature of the invention, how to make, and how to use the invention,
and the more predictable the art is, the less information needs
to be explicitly stated in the specification. In contrast, if little
is known in the prior art about the nature of the invention and
the art is unpredictable, the specification would need more detail
as to how to make and use the invention in order to be enabling.
The "predictability or lack thereof" in the art refers to the
ability of one skilled in the art to extrapolate the disclosed
or known results to the claimed invention. If one skilled in the
art can readily anticipate the effect of a change within the subject
matter to which the claimed invention pertains, then there is predictability
in the art. On the other hand, if one skilled in the art cannot
readily anticipate the effect of a change within the subject matter
to which that claimed invention pertains, then there is lack of
predictability in the art. Accordingly, what is known in the art
provides evidence as to the question of predictability. In particular,
the court in In re Marzocchi, 439 F.2d 220, 223-24, 169
USPQ 367, 368-70 (CCPA 1971), stated:
[i]n the field of chemistry generally, there may be times when
the well-known unpredictability of chemical reactions will alone
be enough to create a reasonable doubt as to the accuracy of
a particular broad statement put forward as enabling support
for a claim. This will especially be the case where the statement
is, on its face, contrary to generally accepted scientific principles.
Most often, additional factors, such as the teachings in pertinent
references, will be available to substantiate any doubts that
the asserted scope of objective enablement is in fact commensurate
with the scope of protection sought and to support any demands
based thereon for proof. [Footnote omitted.]
The predictability in the art is inversely related to the amount
of guidance or direction needed for enablement. In other words,
art areas that are predictable require less guidance or direction
for enablement than art areas that are not predictable. In re
Fisher, 427 F.2 833, 839, 166 USPQ 18, 24 (CCPA 1970).
i. How to Make
(a) One Method is Sufficient
As long as the specification discloses at least one method for
making and using the claimed invention that bears a reasonable
correlation to the entire scope of the claim, then the enablement
requirement of Section 112 is satisfied. In re Fisher, 427
F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). Failure to disclose
other methods by which the claimed invention may be made does not
render a claim invalid under Section 112. Spectra-Physics, Inc.
v. Coherent, Inc. 827 F.2d 1524, 1533, 3 USPQ2d 1737, 1743
(Fed. Cir.), cert. denied, 484 U.S. 954 (1987).
Naturally, for unstable and transitory chemical intermediates,
the "how to make" requirement does not require that the applicant
teach how to make the claimed product in stable, permanent or isolatable
form. In re Breslow, 616 F.2d 516, 521, 205 USPQ 221, 226
(CCPA 1980).
(b) Availability of Starting Materials and Apparatus
A key issue that can arise when determining whether the specification
is enabling is whether the starting materials or apparatus necessary
to make the invention are available. This is often true when the
product or process requires a particular strain of microorganism
and when the microorganism is available only after extensive screening.
The CCPA in In re Ghiron, 442 F.2d 985, 991, 169 USPQ 723,
727 (CCPA 1971), made clear that if the practice of a method requires
a particular apparatus, the application must provide a sufficient
disclosure of the apparatus if the apparatus is not readily available.
The same can be said if certain chemicals are required to make
a compound or practice a chemical process. In re Howarth, 654
F.2d 103, 105, 210 USPQ 689, 691 (CCPA 1981).
The problem with the availability of starting materials when the
product or process requires the use of a particular strain of microorganisms
is addressed in separate training materials relating to depositing
a sample of a microorganism with an independent depository.
(c) Isolated DNA for Purified Protein (In re Deuel)
When claims are directed to any purified and isolated DNA sequence
encoding a specifically named protein wherein the protein has a
specifically identified sequence, a scope rejection is generally
not appropriate.
In In re Deuel, 51 F.3d 1552, 1560, 34 USPQ2d 1210, 1216
(Fed. Cir. 1995), the court stated:
Because Deuel's patent application does not describe how to
obtain any DNA except the disclosed cDNA molecules, claims 4
and 6 may be considered to be inadequately supported by the disclosure
of the application. See generally Amgen Inc. v. Chugai Pharmaceutical
Co., 927 F.2d 1200, 1212-24, 18 USPQ2d 1016, 1026-28 (Fed.
Cir.) (generic DNA sequence claims held invalid under 35 U.S.C. § 112,
first paragraph), cert. denied, 502 U.S. 856 (1991); In
re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970)
(Section 112 "requires that the scope of the claims must bear
a reasonable correlation to the scope of enablement provided
by the specification to persons of ordinary skill in the art").
As this issue is not before us, however, we will not address
whether claims 4 and 6 satisfy the enablement requirement of § 112,
first paragraph, but will leave to the PTO the question whether
any further rejection is appropriate.
The court in Deuel left it to the PTO to decide whether
a scope rejection would be appropriate. Responsive to the issue
left open by the Federal Circuit in Deuel, the PTO has decided
that scope rejections like those noted above should not be advanced
for claims like those in Deuel.
The Deuel claims 4 and 6 were directed to any DNA that
would encode a specific amino acid sequence. Claims 4 and 6 recited
only one amino acid sequence each and each claim was directed to
all nucleic acid sequences that encode the respective amino acid
sequence. The various genetic codes are well-known. Thus, to list
all cDNA of the sequences that encode a given amino acid sequence
simply requires reverse translating the amino acid sequence to
the nucleic acid sequence. Theoretically, one armed only with a
pencil, paper, and the genetic code could list all of the cDNA
that encode the two amino acid sequences mentioned in the claims.
Admittedly, this could not be done in practice even by a fast computer
because claim 4 embraces 2.09 x 1075 embodiments. However, any
one of the embodiments could be readily determined. As to actually
obtaining the cDNA, this could be done by simply writing down the
sequence and ordering it from a company that custom synthesizes
DNA.
ii. How to Use
If a statement of utility in the specification contains within
it a connotation of how to use, and/or the art recognizes that
standard modes of administration are known and contemplated, 35
U.S.C. Section 112, is satisfied. In re Johnson, 282 F.2d
370, 373, 127 USPQ 216, 219 (CCPA 1960); and In re Hitchings,
342 F.2d 80, 87, 144 USPQ 637, 643
(CCPA 1965); see also In re Brana, 51 F.2d 1560,
1566, 34 USPQ2d 1437, 1441 (Fed. Cir. 1993).
It is not necessary to specify the dosage or method of use if
it is known to one skilled in the art that such information could
be obtained without undue experimentation. If one skilled in the
art, based on knowledge of compounds having similar physiological
or biological activity, would be able to discern an appropriate
dosage or method of use without undue experimentation, this would
be sufficient to satisfy 35 U.S.C. Section 112. The applicant need
not demonstrate that the invention is completely safe. See also 35
U.S.C. Section 103 , Utility Guidelines.
(a) Use Recited in the Claims
When a compound or composition claim is limited by a particular
use, enablement of that claim should be evaluated based on that
limitation. See In re Vaeck, 947 F.2d 488, 495, 20
USPQ2d 1438, 1444 (Fed. Cir. 1991)(claiming a chimeric gene capable
of being expressed in any cyanobacterium and thus defining the
claimed gene by its use).
In contrast, when a compound or composition claim is not limited
by a recited use, any enabled use that would reasonably correlate
with the entire scope of that claim is sufficient to preclude a
rejection for non-enablement based on how to use. If multiple uses
for claimed compounds or compositions are disclosed in the application,
then an enablement rejection must include an explanation, sufficiently
supported by the evidence, why the specification fails to enable
each disclosed use. In other words, if any use is enabled when
multiple uses are disclosed, the application is enabling for the
claimed invention.
The following examples illustrate the application of these standards.
- The claim: A composition for treating Alzheimer's disease comprising
a compound having the formula X" (where X is specifically defined
within the claim). Assuming it is clear from the specification
and/or applicant's arguments that the claimed composition is
limited to treating Alzheimer's disease, the enablement issue
is whether one skilled in the art could have made or used the
composition for treating Alzheimer's disease without undue experimentation,
at the time the application was filed. The enablement analysis
should be based on whether there is evidence that one skilled
in the art could not have used the compound for treating Alzheimer's
disease without undue experimentation. If the statement of use
is only a statement of one intended use, then the claim should
be treated as in example 2.
- The claim: A composition comprising a compound having the formula
X (where X is specifically defined within the claim). The enablement
issue is whether one skill in the art could have made or used
the composition for any disclosed or well-established use without
undue experimentation, at the time the application was filed.
The enablement analysis should be based on whether there is evidence
that one skilled in the art could not have used the compound
for any disclosed or well-established use undue experimentation.
- The claim: A composition comprising a compound having the formula
X in a pharmaceutically acceptable carrier (where X is specifically
defined within the claim). The specification discloses both an in
vitro and in vivo use for the composition.
The presence of the phrase "pharmaceutically acceptable" in combination
with the disclosed in vivo use implies some pharmaceutical
use. Therefore, the initial enablement analysis should be
based on whether there is any evidence that one skilled in art
could not use the compound for any disclosed or well-established
pharmaceutical use, i.e., treatment of some disease or condition in
vivo, without undue experimentation. Any subsequent enablement
analysis should be based on the claim language, what is taught
in the specification, as well as any rebuttal arguments.
All rebuttal arguments must be considered. The weight the evidence
and each argument should be given will depend on the facts of the
case. Assuming that the applicants rebuttal is persuasive, the
35 U.S.C. Section 112, first paragraph, rejection should be withdrawn.
The persuasiveness of any evidence and arguments clearly depends
on the specific language of the claim, the teachings in the specification
and the evidence submitted in rebuttal to the rejection.
(b) Diagnosis Assays
Unless a specification specifically states something to the contrary,
the term "diagnostic assay" is to be construed to mean any assay
that can be used to help diagnose a condition, as opposed to an
assay that can, in and of itself, diagnose a condition. A diagnosis
is typically made by evaluating the results of several screening
assays, each of which has some level of false results and, accordingly,
each of the screening assays would be a "diagnostic assay". Therefore,
to enable a diagnostic assay use, a disclosure merely needs to
teach how to make and use the assay for screening purposes.
© Several Decisions Ruling that the Disclosure was Non-Enabling
The following summaries should not be relied upon to support a
case of lack of enablement without carefully reading the case.
- In In re Wright, 999 F.2d 1557, 27 USPQ2d 1510 (Fed.
Cir. 1993), the 1983 application disclosed a vaccine against
the RNA tumor virus known as Prague Avian Sarcoma Virus, a member
of the Rous Associated Virus family. Using functional language,
Wright claimed a vaccine "comprising an immunologically effective
amount" of a viral expression product. Id. at 1559, 27
USPQ2d at 1511. Rejected claims covered all RNA viruses as well
as to avian RNA viruses. The Examiner provided a teaching that
in 1988, a vaccine for another retrovirus (i.e., AIDS) remained
an intractable problem. This evidence, along with evidence that
the RNA viruses were a diverse and complicated genus, convinced
the Federal Circuit that the invention was not enabled for either
all retroviruses or even for avian retroviruses.
- In In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed.
Cir. 1993), a 1985 application functionally claimed a method
of producing protein in plant cells by expressing a foreign gene.
The court stated: "[n]aturally, the specification must teach
those of skill in the art 'how to make and use the invention
as broadly as it is claimed.'" Id. at 1050, 29 USPQ2d
at 2013. Although protein expression in dicotyledonous plant
cells was enabled, the claims covered any plant cell. The examiner
provided evidence that even as late as 1987, use of the claimed
method in monocot plant cells was not enabled. Id. at
1051, 29 USPQ2d at 2014.
- In In re Vaeck, 947 F.2d 488, 495, 20 USPQ2d 1438, 1444
(Fed. Cir. 1991), the court found that several claims were not
supported by an enabling disclosure "[t]aking into account the
relatively incomplete understanding of the biology of cyanobacteria
as of appellant's filing date, as well as the limited disclosure
by appellants of the particular cyanbacterial genera operative
in the claimed invention. . . ." The claims at issue were not
limited to any particular genus or species of cyanbacteria and
the specification mentioned nine genera and the working examples
employed one species of cyanobacteria.
- In In re Colianni, 561 F.2d 220, 222-23,195 USPQ 150,
152 (CCPA 1977), where the court affirmed a rejection under Section
112, first paragraph, because the specification directed to a
method of mending a fractured bone by applying "sufficient" ultrasonic
energy to the bone did not define a "sufficient" dosage or teach
one of ordinary skill how to select the appropriate intensity,
frequency, or duration of the ultrasonic energy.
(d) Several Decisions Ruling that the Disclosure was Enabling
The following summaries should not be relied upon to support a
case of lack of enablement without carefully reading the case.
- In PPG Ind. v. Guardian Ind., 75 F.3d 1558, 1564, 37
USPQ2d 1618, 1623 (Fed. Cir. 1996), the court ruled that even
though there was a software error in calculating the ultraviolet
transmittance data for examples in the specification making it
appear that the production of a cerium oxide-free glass that
satisfied the transmittance limitation would be difficult, the
specification indicated that such glass could be made. The specification
was found to indicate how to minimize the cerium content while
maintaining low ultraviolet transmittance.
- In In re Wands, 858 F.2d 731, 8 USPQ2d 1400 (Fed. Cir.
1988), the court reversed the rejection for lack of enablement
under Section 112, first paragraph, concluding that undue experimentation
would not be required to practice the invention. The nature of
monoclonal antibody technology is such that experiments first
involve the entire attempt to make a monoclonal hybridomas to
determine which ones secrete antibody with the desired characteristics.
The court found that the specification provided considerable
direction and guidance on how to practice the claimed invention
and presented working examples, that all of the methods needed
to practice the invention were well known, and that there was
a high level of skill in the art at the time the application
was filed. Furthermore, the applicant carried out the entire
procedure for making a monoclonal antibody against HBsAg three
times and each time was successful in producing at least one
antibody which fell within the scope of the claims.
- In In re Bundy, 642 F.2d 430, 434, 209 USPQ 48, 51-52
(CCPA 1981), the court ruled that the claimed analogs of naturally
occurring prostaglandins had certain pharmacological properties
even though the specification lacked any examples of specific
dosages, but did state that the novel compound possessed activity
similar to E-type prostaglandins.
c. Presence or Absence of Working Examples (Make or Use)
The presence of a working examples demonstrates the making or
using of the invention. However, working examples are not required
by the statute, rules, or the case law.
i. None or One Working Example
The lack of working examples is one consideration in the overall
analysis of lack of enablement. In re Colianni, 561 F.2d
at 224, 195 USPQ at 153. The MPEP, Section 2164.02, states: "[t]he
specification need not contain an example if the invention is otherwise
disclosed in such manner that one skilled in the art will be able
to practice it without an undue amount of experimentation."
When considering the factors relating to a determination of non-enablement,
if all the other factors point toward enablement, then the absence
of working examples will not by itself render the invention non-enabled.
In other words, lack of working examples or lack or evidence that
the claimed invention works as described should never be the sole
reason for rejecting the claimed invention on the grounds of lack
of enablement. A single working example in the specification for
a claimed invention is enough to preclude a rejection which states
that nothing is enabled since at least that embodiment would be
enabled. However, a rejection stating that enablement is limited
to a particular scope may be appropriate.
The presence of only one working example should never be the sole
reason for making a scope rejection, even though it is a factor
to be considered along with all the other factors. To make a valid
rejection, one must evaluate all the facts and evidence and state
why one would not expect to be able to extrapolate that one example
across the entire scope of the claims.
ii. Correlation: In Vitro/In Vivo
The issue of "correlation" is related to the issue of the presence
or absence of working examples. "Correlation" for purposes of this
portion of the training materials refers to the relationship between in
vitro or in vivo animal model assays and a disclosed
or a claimed method of use. An in vitro or in vivo animal
model example in the specification, in effect, constitutes a "working
example" if that example "correlates" with a disclosed or claimed
method invention. If there is no correlation, then the examples
do not constitute "working examples." In this regard, the issue
of "correlation" is also dependent on the state of the prior art.
In other words, if the art is such that a particular model is recognized
as correlating to a specific condition, then it should be accepted
as correlating unless the examiner has evidence that the model
does not correlate. Even with such evidence, the examiner must
weigh the evidence for and against correlation and decide whether
one skilled in the art would accept the model as reasonably correlating
to the condition. In re Brana, 51 F.3d 1560, 1566, 34 USPQ2d
1436, 1441 (Fed. Cir. 1995)(reversing the PTO decision based on
finding that in vitro data did not support in vivo applications).
Since the initial burden is on the examiner to give reasons for
the lack of enablement, when possible to supported by evidence,
the examiner must also give reasons for a conclusion of lack of
correlation for an in vitro or in vivo animal model
example. A rigorous or an invariable exact correlation is not required,
as stated in Cross v. Iizuka, 753 F.2d 1040, 1050, 224 USPQ
739, 747 (Fed. Cir. 1985):
based upon the relevant evidence as a whole, there is a reasonable
correlation between the disclosed in vitro utility and
an in vivo activity, and therefore a rigorous correlation
is not necessary where the disclosure of pharmacological activity
is reasonable based upon the probative evidence. (Citations omitted.)
iii. Working Examples and a Claimed Genus
For a claimed genus, representative examples together with a statement
applicable to the genus as a whole will ordinarily be sufficient
if one skilled in the art-in view of level of skill, state of the
art and the information in the specification-would expect the claimed
genus could be used in that manner without undue experimentation.
Proof of enablement will be required for other members of the claimed
genus only where adequate reasons are advanced by the examiner
to establish that a person skilled in the art could not use the
genus as a whole without undue experimentation.
d. Quantity of Experimentation
The quantity of experimentation needed to be performed by one
skilled in the art is only one factor involved in determining whether "undue
experimentation" is required to make and use the invention. "[A]n
extended period of experimentation may not be undue if the skilled
artisan is given sufficient direction or guidance." In re Colianni,
561 F.2d at 224,195 USPQ at 153. "'The test is not merely quantitative,
since a considerable amount of experimentation is permissible,
if it is merely routine, or if the specification in question provides
a reasonable amount of guidance with respect to the direction in
which the experimentation should proceed.' In re Wands,
858 F.2d at 737, 8 USPQ2d at 1404 (citing In re Angstadt,
537 F.2d 489, 502-04, 190 USPQ 214, 218 (CCPA 1976)). Time and
expense are merely factors in this consideration and are not the
controlling factors. United States v. Telectonics Inc., 857
F.2d 778, 785, 8 USPQ2d 1217, 1223 (Fed. Cir. 1988), cert.
denied, 490 U.S. 1046 (1989).
In the chemical arts, the guidance and ease in carrying out an
assay to achieve the claimed objectives may be an issue to be considered
in determining the quantity of experimentation needed. For example,
if a very difficult and time consuming assay is needed to identify
a compound within the scope of a claim, then this great quantity
of experimentation should be considered in the overall analysis.
Time and difficulty of experiments are not determinative if they
are merely routine. Quantity of examples is only one factor that
must be considered before reaching the final conclusion that undue
experimentation would be required. In re Wands, 858 F.2d
at 737, 8 USPQ2d at 1404.
i. Example of Reasonable Experimentation
In United States v. Telectonics Inc., 857 F.2d 778, 8 USPQ2d
1217 (Fed. Cir. 1988), cert. denied, 490 U.S. 1046 (1989),
the court reversed the findings of the district court for lack
of clear and convincing proof that undue experimentation was needed.
The court ruled that since one embodiment (stainless steel electrodes)
and the method to determine dose/response was set forth in the
specification, the specification was enabling. The question of
time and expense of such studies, approximately $50,000 and 6-12
months standing alone, failed to show undue experimentation.
ii. Example of Unreasonable Experimentation
In In re Ghiron, 442 F.2d at 991-92, 169 USPQ at 727-28,
functional "block diagrams" were insufficient to enable a person
skilled in the art to practice the claimed invention with only
a reasonable degree of experimentation because the claimed invention
required a "modification to prior art overlap computers," and because "many
of the components which appellants illustrate as rectangles in
their drawing necessarily are themselves complex assemblages .
. . . It is common knowledge that many months or years elapse from
the announcement of a new computer by a manufacturer before the
first prototype is available. This does not bespeak of a routine
operation but of extensive experimentation and development work
. . . ."
e. Supplementing a Disclosure
The specification may be enabling even though amendments may be
needed. Such amendments often occur when the applicant incorporates
information by reference into the specification or uses a trade
name or trademark to provide descriptive information.
i. Incorporating by Reference
The Commissioner has considerable discretion to permit the applicant
to incorporate information by reference into the specification.
The information incorporated by reference at the time of filing
is as much a part of the application as filed as if the text were
repeated therein. Editing the application by inserting verbatim
that which was previously only incorporated by reference does not
raise new matter issues. In re Hawkins, 486 F.2d 569, 574,
179 USPQ 157, 161 (CCPA 1973); and MPEP Sections 608.01(p) and
2163.07(b).
ii. Use of Trademarks: Potential4Future Non-enablement
When the applicant refers to materials, products or processes,
etc. by their respective trade name or trademark in the specification,
the examiner should require that a generic description be inserted
in place of, or in addition to, a trade name or trademark. This
is necessary since the owner of the product to which the trade
name or trademark refers can change the product over time. Such
future decisions are often outside the control of the applicant.
If such a change occurred, the trade name or trademark could come
to represent different things at different points in time with
no way learning what the differences were. Whether the use of a
trade name or trademark provides sufficient description and disclosure
of the claimed invention must be decided on a case-by-case basis.
Where the identification material or apparatus referred to by its
trademark or trade name is introduced by amendment, the information
must be restricted to the characteristics of the product known
at the time the application was filed to avoid any question of
new matter. In re Metcalfe, 410 F.2d 1378, 1382, 161 USPQ
789, 792 (CCPA 1969); and MPEP Section 608.01(v).
B. UTILITY AND OPERABILITY
1. Preferred Materials in Specification Need
not be in the Claims
Limiting an applicant to the preferred materials in the absence
of limiting prior art would not serve the constitutional purpose
of promoting the progress in the useful arts. Therefore, an enablement
rejection based on the grounds that a disclosed critical limitation
is missing from a claim should be made only when the language of
the specification makes it clear that the limitation is critical
for the invention to function as intended. Broad language in the
disclosure, including the abstract, omitting an allegedly critical
feature, tends to rebut the argument of criticality.
2. Inoperability/Inoperative Species within
the Scope of the Claim
The presence of inoperative embodiments within the scope of a
claim does not necessarily render a claim nonenabled. The standard
is whether a skilled person could determine which embodiments that
were conceived, but not yet made, would be inoperative or operative
with expenditure of no more effort than is normally required in
the art. Atlas Powder Co. v. E.I. duPont de Nemous & Co.,
750 F.2d 1569, 1577, 224 USPQ 409, 414 (Fed. Cir. 1984)(prophetic
examples do not make the disclosure non-enabling). Although, typically,
inoperative embodiments are excluded by language in a claim the
scope of the claim may still not be enabled where undue experimentation
is involved in determining those embodiments that are operable.
A disclosure of a large number of operable embodiments and the
identification of a single inoperative embodiment did not render
a claim broader than the enabled scope because undue experimentation
was not involved in determining those embodiments that were operable. In
re Angstadt, 537 F.2d 498, 502-03, 190 USPQ 214, 218 (CCPA
1976); and MPEP Section 2164.08(b). However, claims reading on
significant numbers of inoperative embodiments would render claims
nonenabled when the specification does not clearly identify the
operative embodiments and undue experimentation is involved in
determining those that are operative. Atlas Powder Co. v. E.I.
duPont de Nemous & Co., 750 F.2d 1569, 1577, 224 USPQ 409,
414 (Fed. Cir. 1984); In re Cook, 439 F.2d 730, 735, 169
USPQ 298, 302 (CCPA 1971); see also MPEP Section 2164.08(b).
C. LACK OF ENABLEMENT IN VIEW OF AN OBVIOUSNESS
REJECTION
Many times an Office action will contain both a 35 U.S.C. Section
112, first paragraph, enablement rejection and a prior art rejection
under 35 U.S.C. Section 102 and/or 103 against the same claim.
In such cases, the examiner has determined that the claimed invention
is not enabled and yet is anticipated or prima facie obvious in
view of prior art. The presence of both rejections in an Office
action against the same claim appears contradictory. However, it
is not necessarily a contradiction or an improper Office action.
The following examples illustrate scenarios where both can coexist.
- A claim recites a genus but the specification is enabling only
for species X. A reference found by the examiner provides evidence
that the specification is enabling for species X only and discloses
species X. In this case, a scope rejection stating that the claims
should be limited to species X is appropriate as is a 102 rejection.
- A claim recites a genus. The specification discloses only one
use for the genus and demonstrates only species X for that use.
The examiner finds a first reference that supports the position
that it would require undue experimentation to use members of
that genus other than species X for the only disclosed purpose.
The examiner also finds a second reference that suggests another
member, species Y, of the genus for a different purpose. In this
case, a scope rejection stating that the claim should be limited
to species X is appropriate as is a Section 103 rejection stating
that species Y would have been obvious. These rejections are
not contradictory.
- A claim recites a method of treating HIV infection in a human
by administering X to the human. The specification discloses
an in vitro assay which demonstrates that X will inhibit
HIV replication. The examiner finds five references to support
the position that treating HIV is unpredictable and that in
vitro models do not reasonably correlate to in vivo treatment.
The examiner also finds a sixth reference that demonstrates that
X will inhibit HIV replication in vitro and suggests treating
HIV infection in a human byadministering X to the human. In this
case, a lack of enablement rejection would be appropriate using
the five references as support. A Section 103 rejection using
the sixth reference would also be appropriate. Admittedly, the
rejections are contradictory. Nevertheless, in view of the contradictory
nature of the suggestions in the state of the art, the contradictory
rejections are appropriate since one position is likely to be
correct. This type of treatment should be limited to those art
areas in which the teachings and suggestions in the art are in
conflict with one another.
D. THE INVENTION MAY BE ENABLED BUT NOT ADEQUATELY
DESCRIBED
The enablement requirement of 35 U.S.C. Section 112, first paragraph,
is separate and distinct from the description requirement. Vas
Cath Inc. v. Mahurkar, 935 F.2d 1555, 1563, 19 USPQ2d
1111, 1116-17 (Fed. Cir. 1991)("the purpose of the 'written description'
requirement is broader than to merely explain how to 'make and
use'"); and MPEP Section 2161. Therefore, the fact that an additional
limitation to a claim may lack descriptive support in the disclosure
as originally filed does not necessarily mean that the limitation
is also not enabled. In other words, the statement of a new limitation
in and of itself may enable one skilled in the art to make and
use the claim containing that limitation even though that limitation
may not be described in the original disclosure. Consequently,
such limitations must be analyzed for both enablement and description
using their separate and distinct criteria.
Furthermore, when the subject matter is not in the specification
portion of the application as filed but is in the claims, the limitation
in and of itself may enable one skilled in the art to make and
use the claim containing the limitation. When claimed subject matter
is only presented in the claims and not in the specification portion
of the application, the specification should be objected to for
lacking the requisite support for the claimed subject matter using
Form Paragraph 7.44. See MPEP Section 2163.06. This is a
technical rejection only and enablement issues should be treated
separately.
Form Paragraph 7.44 provides:
CLAIMED SUBJECT MATTER NOT IN SPECIFICATION
The specification is objected to as failing to provide proper
antecedent basis for the claimed subject matter. See 37 CFI 1.75(d)(1)
and MPEP 608.01(1). Correction of the following is required: [1].
IV. COMMUNICATING FINDINGS TO THE APPLICANT
A.THE LEVEL OF DETAIL
While the analysis and conclusion are based on all the above factors
and the evidence as a whole, it is not necessary to discuss each
factor in the written enablement rejection. The language should
focus on those factors, reasons, and evidence that lead the examiner
to conclude that the specification fails to teach how to make
and use the claimed invention without undue experimentation,
or that the scope of any enablement provided to one skilled in
the art is not commensurate with the scope of protection sought
by the claims. This can easily be done by making specific findings
of fact, supported by the evidence, and then drawing conclusions
based on these findings of fact. For example, doubt may arise about
enablement because information is missing about one or more essential
parts or relationships between parts which one skilled in the art
could not develop without undue experimentation. In such a case,
the examiner should specifically identify what information is missing
and why one skilled in the art could not supply the information
without undue experimentation. MPEP § 2164.06. References should
be supplied if possible to support a prima facie case of
lack of enablement, but are not always required. In re Marzocchi,
439 F.2d 220, 224, 169 USPQ 367, 370 (CCPA 1971). However, specific
technical reasons are always required.
In accordance with the principles of compact prosecution, if an
enablement rejection is appropriate, the first Office action on
the merits should present the best case with all the relevant reasons,
issues, and evidence so that all such rejections can be withdrawn
if applicant provides appropriate convincing arguments and/or evidence
in rebuttal. Providing the best case in the first Office action
will also allow the second Office action to be made final should
applicant fail to provide appropriate convincing arguments and/or
evidence. Citing new references and/or expanding arguments in a
second Office action could prevent that Office action from being
made final. The principles of compact prosecution also dictate
that if an enablement rejection is appropriate and the examiner
recognizes limitations that would render the claims enabled, the
examiner should note such limitations to applicant as early in
the prosecution as possible.
In other words, the examiner should always look for enabled,
allowable subject matter and communicate to applicant what
that subject matter is at the earliest point possible in the
prosecution of the application.
B. THE FORM PARAGRAPHS
The relevant form paragraphs that should be used when making a
rejection for lack of enablement are paragraphs 7.31.02, 7.31.03,
or 7.33.01. See MPEP § 706.03©. Regardless of which Form
paragraph is used, the examiner must always clearly articulate
the reasons for his or her belief that an enablement issue exists
and cite to the evidence that supports his or her belief.
1 35 U.S.C. 112,1st, Enablement 7.31.02
Form paragraph 7.31.02 is to be used when it is the examiner's
position that nothing within the scope of the claims is enabled.
In such a rejection, the examiner should explain all the
reasons why nothing within the scope of the claims is enabled.
To make sure all relevant issues are raised, this should include
any issues regarding the breadth of the claims relative to the
guidance in the disclosure. Form paragraph 7.31.02 is as follows:
Claim [1] rejected under 35 U.S.C. 112, first
paragraph, because the specification does not enable any person
skilled in the art to which it pertains, or with which it is most
nearly connected, to [2] the invention. [3].
Examiner Note:
- If the problem is one of scope, form paragraph 7.31.03 should
be used.
- In bracket 2, fill in only the appropriate portion of the
statute, i.e., one of the following "make," "use," or "make
and use".
- In bracket 3, identify the claimed subject matter for which
the specification is not enabling along with an explanation
as to why the specification is not enabling. The explanation
should include any questions posed by the examiner which were
not satisfactorily resolved and consequently raise doubt as
to enablement.
- Where an essential component or step of the invention is
not recited in the claims, use form paragraph 7.33.01.
2. 35 U.S.C. 112, 1st, Scope Of Enablement 7.31.03
Form paragraph 7.31.03 is to be used when it is the examiner's
position that something within the scope of the claims is enabled
but the claims are not limited to that scope. Form paragraph 7.31.03
states:
Claim [1] rejected under 35 U.S.C. 112, first
paragraph, because the specification, while being enabling for [2],
does not reasonably provide enablement for [3]. The specification
does not enable any person skilled in the art to which it pertains,
or with which it is most nearly connected, to [4] the invention
commensurate in scope with these claims. [5].
Examiner Note:
- This paragraph is to be used when the scope of the claims
is not commensurate with the scope of the enabling disclosure.
- In bracket 2, identify the claimed subject matter for which
the specification is enabling. This may be by reference to
specific portions of the specification.
- In bracket 3, identify aspect(s) of the claims(s) for which
the specification is not enabling.
- In bracket 4, fill in only the appropriate portion of the
statute, i.e., one of the following: "make," "use," or "make
and use".
- In bracket 5, identify the problem along with an explanation
as to why the specification is not enabling. The explanation
should include any questions posed by the examiner which were
not satisfactorily resolved and consequently raise doubt as
to enablement.
3. 35 U.S.C. 112, 1st, Essential Subject
Matter Missing From Claims (Enablement) , 7.33.01 :
Form paragraph 7.33.01 is to be used when it is the examiner's
position that a feature that is critical or essential to the practice
of the claimed invention is missing from the claim.
Form paragraph 7.33.01 states:
Claim [1] rejected under 35 U.S.C. 112, first
paragraph, as based on a disclosure which is not enabling. [2] critical
or essential to the practice of the invention, but not included
in the claim(s) is not enabled by the disclosure. In re Mayhew,
527 F.2d 1229, 188 USPQ 356 (CCPA 1976). [3].
Examiner Note:
- In bracket 2, recite the subject matter omitted from the
claims.
- In bracket 3, give the rationale for considering the omitted
subject matter critical or essential.
- The examiner shall cite the statement, argument, date, drawing,
or other evidence which demonstrates that a particular feature
was considered essential by the applicant, is not reflected
in the claims which are rejected.
4. Multiple Use of Form Paragraphs
A claim should not be rejected using form paragraph 7.31.02 and
also rejected using either form paragraph 7.31.03 or form paragraph
7.33.01 within the same Office action since this would present
conflicting and confusing positions. Form paragraph 7.31.02 states
that nothing is enabled in that claim and each of the other two
form paragraphs state that something within the scope of the claim
is enabled. If the examiner concludes that nothing is enabled for
one reason and that the breadth of the claims is also not commensurate
in scope with the guidance in the specification, then all these
issues should be raised with respect to that claim using form paragraph
7.31.02. Sometimes the scope of a claim may not be enabled because
a critical or essential feature is missing in addition to other
reasons. In such cases, all the scope issues may be raised under
form paragraph 7.31.03 or form paragraph 7.33.01, or the issues
may be raised separately by using both form paragraph 7.31.03 and
form paragraph 7.33.01.
5. Practical Tips in Writing the Rejection
V. REBUTTAL TO THE REJECTION PROOF OF ENABLEMENT:
EVIDENCE AND ATTORNEY ARGUMENT
Once the examiner has weighed all the evidence and established
a reasonable basis to question the enablement provided for the
claimed invention, the burden falls on applicant to present persuasive
arguments, supported by suitable proofs where necessary, that one
skilled in the art would be able to make and use the claimed invention
using the application as a guide. The evidence provided by applicant
need not be conclusive but merely convincing to one
skilled in the art. A declaration or affidavit is, itself, evidence
that must be considered.
To overcome a prima facie case of lack of enablement, applicant
must demonstrate by argument and/or evidence that the disclosure, as
filed, would have enabled the claimed invention for one skilled
in the art at the time of filing. This does not preclude applicant
from providing a declaration after the filing date which demonstrates
that the claimed invention works. However, the examiner should
carefully compare the steps, materials, and conditions used in
the experiments of the declaration with those disclosed in the
application to make sure that they are commensurate in scope, i.e.,
that the experiments used the guidance in the specification as
filed and what was well known to one of skill in the art. Such
a showing also must be commensurate with the scope of the claimed
invention, i.e., must bear a reasonable correlation.
The examiner must then weigh all the evidence before him or her,
including the specification and any new evidence supplied by applicant
with the evidence and/or sound scientific reasoning previously
presented in the rejection and decide whether the claimed invention
is enabled. The examiner should never make the determination
based on personal opinion. The determination should always be based
on the weight of all the evidence.
A. USE OF POST FILING DATE EVIDENCE
In general, if an applicant seeks to use a patent to prove the
state of the art for the purpose of the enablement requirement,
the patent must have an issue date earlier than the effective filing
date of the application. In re Budnick, 537 F.2d 535, 538,
190 USPQ 422, 424 (CCPA 1976). Similarly, in general, the examiner
should not use post-filing date references to demonstrate that
the patent is non-enabling. Exceptions to these rules could occur
if a later-dated reference provides evidence of what one skilled
in the art would have known on or before the effective filing date
of the patent application. That is, if individuals of skill in
the art state that a particular invention is not possible years
after the filing date, that would be evidence that the disclosed
invention was not possible at the time of filing and should be
considered.
B. EXPERT DECLARATIONS
Declarations and affidavits are evidence. The weight to
give them will depend upon the amount of factual evidence they
contain to support the conclusion of enablement. In re Buchner, 929
F.2d 660, 661, 18 USPQ2d 1331, 1332 (Fed. Cir. 1991)("expert's
opinion on the ultimate legal conclusion must be supported by something
more than a conclusory statement"); cf. In re
Alton, 76 F.3d 1168, 1174, 37 USPQ2d 1578, 1583 (Fed. Cir.
1996)(declarations relating to the written description requirement
should have been considered).
C. USE OF FDA SUBMISSIONS
An applicant may argue that the FDA has approved clinical trials
and, therefore, the claims should be considered enabled by the
specification. FDA approval is an important consideration. However,
considerations made by the FDA for approving clinical trial are
different from those made by the PTO in determining whether a claim
is enabled. See Scott v. Finney, 34 F.3d 1058, 1063,
32 USPQ2d 1115, 1120 (Fed. Cir. 1994) ("[t]esting for full safety
and effectiveness of a prosthetic device is more properly left
to the [FDA].")
Applicant should be encouraged to provide any evidence to demonstrate
that the disclosure enables the claimed invention, including evidence
actually submitted to the FDA to obtain approval for clinical trials.
Once that evidence is submitted, it must be weighed with all other
evidence according to the standards set forth above so as to reach
a determination as to whether the disclosure enables the claimed
invention.
ENABLEMENT DECISION TREE
![Enablement Decision Tree Diagram [link to full text]](images/tree.gif)
Example A: Hybridization Probes I
Specification: The specification discloses that bacteria
A is known to cause a specific disease and, therefore, detection
of bacteria A in a sample is desirable. The specification even
discloses that methods are known which detect bacteria A in a sample
via culturing techniques. According to the specification, such
detection methods are difficult to perform and therefore detection
methods using nucleic acid probes are preferred.
The specification discloses that one object of the invention is
to provide nucleic acids complementary to unique nucleic acid sequences
within the RNA or DNA of bacteria A and which can be used to detect
bacteria A. Another object of the invention is to provide a method
of detecting bacteria A in a sample by contacting the sample with
a probe which preferentially hybridizes to RNA or DNA of bacteria
A but not to non-bacteria A organisms.
The term "probe" is described in the specification as a nucleic
acid between 10 and 300 base pairs in length which contain specific
nucleotide sequences that specifically and preferentially hybridize
under predetermined conditions to nucleic acid sequences of bacteria
A. The probes optionally contain a detectable moiety.
The following three specific probes were disclosed:
Bacteria A probe 1 (35mer) (SEQ ID NO:1)
5'-CATTAGAGTC GTACGTGCTA GACTGATTAA CCGGT-3'
Bacteria A probe 2 (33mer) (SEQ ID NO:2)
5'-CAATCCAGTA AGTTTTACCC GGCCAAATAA AGG-3'
Bacteria A probe 3 (30mer) (SEQ ID NO:3)
5'-AAATAGCCAG ATCATTGCCC CGGACCCTTG-3'
An example appears in the specification which demonstrates how
to carry out the detection and which shows that the three probes
are specific for bacteria A and fail to hybridize to 50 other types
of bacteria.
Claims:
- An isolated nucleic acid consisting of 10 to 300 nucleotides
which hybridizes preferentially to RNA or DNA of bacteria A and
not to non-bacteria A organisms, wherein said nucleic acid is
or is complementary to a nucleotide sequence comprising at least
ten consecutive nucleotides from a nucleotide sequence selected
from the group consisting of SEQ ID NOS 1, 2, and 3.
- A probe comprising a nucleic acid of claim 1 and a detectable
moiety.
- A method of detecting the presence of bacteria A in a sample
suspected of containing bacteria A comprising
- a) contacting the sample with an isolated nucleic acid of
claim 1,
- b) imposing hybridization conditions on the sample and said
isolated nucleic acid to allow the formation of a hybridization
product between said nucleic acid and RNA or DNA from bacteria
A, if present in the sample, but not from RNA or DNA from non-bacteria
A bacteria; and
- c) detecting any hybridization product as an indication of
the presence of bacteria A in the sample.
State of the Prior Art: A search was carried out to compare
the multitude of 10 nucleotide probes encompassed by the claims
with sequences in the EMBL database with the following results:
- 10,541 database hits for the 10mers of probe 1;
- 15,378 database hits for the 10mers of probe 2;
- 5,691 database hits for the 10mers of probe 3.
Some of the hits for each probe were in the RNA or DNA of bacteria
other than bacteria A, such as Salmonella, Candida, and Streptococcus.
Wallace et al, Methods Enzymol. 152:432-443 (1987).
Sambrook et al, Molecular Cloning, A Laboratory Manual,
Second Edition, 1989, Cold Spring Harbor Laboratory, Cold Spring
Harbor, NY, p. 11.47.
Wallace et al and Sambrook et al teach the empirical nature of
determining the specificity of hybridization probes and the unpredictability
of the effect of mismatches within an oligonucleotide probe.
The 50 different bacteria tested within the example in the specification
are representative of bacteria in general.
Analysis:
There is a demonstration in the specification that the three specifically
disclosed probes can be used to detect bacteria A. Furthermore,
the sequences of those probes are disclosed so that one skilled
in the art could clearly make them. Therefore, the specification
does teach how to make and use three embodiments encompassed by
the claims. Accordingly, an objection/rejection using form paragraph
7.31.02 would be inappropriate. The issue then is whether the enabled
embodiments are representative of the scope of the claims.
Before this can be determined, the scope of at least claim 1 must
be determined. Claim 1 recites three limitations on the nucleic
acid, two structural and one functional. The two structural limitations
are 1) that the nucleic acid consists of 10 to 300 nucleotides
and 2) that the nucleic acid is or is complementary to a nucleotide
sequence comprising at least ten consecutive nucleotides
from a nucleotide sequence selected from the group consisting of
SEQ ID NOS 1, 2, and 3. Since the nucleotide sequence mentioned
merely comprises at least ten consecutive nucleotides from
a nucleotide sequence selected from the group consisting of SEQ
ID NOS 1, 2, and 3, it encompasses any random sequence of any length
as long as it has a stretch of at least ten consecutive nucleotides
that is the same as in SEQ ID NOS 1-3. Furthermore, since there
is no limitation that the claimed nucleic acid be complementary
to the nucleotide sequence at the stretch of at least ten consecutive
nucleotides that is the same as in SEQ ID NOS 1-3, the structural
limitations encompass any nucleic acid consisting of 10 to 300
nucleotides. The functional limitation is that the nucleic acid
must be such that is hybridizes preferentially to RNA or DNA of
bacteria A and not to non-bacteria A bacteria. Thus, claim 1 encompasses
any nucleic acid that is 10 to 300 nucleotides in length and hybridizes
preferentially to RNA or DNA of bacteria A and not to non-bacteria
A bacteria.
Clearly if a nucleic acid hybridizes preferentially to RNA or
DNA or bacteria and not to non-bacteria A bacteria, one skilled
in the art would know how to use that nucleic acid based on the
teachings in the specification. Thus, the specification teaches
how to use all the nucleic acids encompassed by the claims. However,
does the specification teach how to identify or make all nucleic
acids that have both the structural limitation and the functional
limitation? The answer in this case would be no since there is
evidence sufficient to rebut the presumption that the full scope
of claim 1 would be enabled without undue experimentation. Specifically,
the state of the prior art as exemplified by Wallace et al and
Sambrook et al is such that determining the specificity of hybridization
probes is empirical by nature and the effect of mismatches within
an oligonucleotide probe is unpredictable. The database search
results suggest that there are probes that would meet the structural
limitations of the claims but not the functional limitation. The
only specific guidance or working example given in the specification
is for the three specific sequences of SEQ ID NOS 1-3 but there
is no suggestion as to what the target sites in bacteria A are
or what modifications can be made while retaining the functional
limitation. The structural limitations of the claims clearly cover
any nucleic acid that is 10 to 300 nucleotides in length (on the
order of 4300 possible nucleic acids). Because of these considerations,
one skilled in the art would have to make and test all nucleic
acids that meet the structural limitations to determine which also
meet the functional limitation. This amount of experimentation
would be impossible in many lifetimes. Therefore, based on the
empirical and unpredictable nature of the invention and state of
the prior art, the limited guidance and working examples in the
specification, and the extensive quantity of experimentation needed
to identify the nucleic acids encompassed by the claims, it would
be reasonable to conclude that it would require an undue amount
of experimentation to identify the nucleic acids encompassed by
the claims. In this case a scope rejection using form paragraph
7.31.03 would be appropriate.
The only issue remaining is the decision as to the scope that
is enabled by the specification. Clearly the three probes used
in the example are enabled. Is this all that is enabled? The answering
of this question can be approached by considering claims having
narrower scope, but still having written descriptive support, and
determining whether the specification enables such a claim. Doing
this, a claim of the following scope would be enabled on the facts
presented here:
An isolated nucleic acid consisting of 10 to 35 nucleotides
which hybridizes preferentially to RNA or DNA of bacteria A and
not to non-bacteria A organisms, wherein said nucleic acid is
or is complementary to a nucleotide sequence consisting of at
least ten consecutive nucleotides from a nucleotide sequence
selected from the group consisting of SEQ ID NOS 1, 2, and 3.
Note, the upper limit of 35 nucleotides has clear descriptive
support based on the fact that one of the specific probes of the
example has 35 nucleotides. Nothing larger than 35, other than
300, has specific descriptive support and an upper limit of 300
would not be enabled for the reasons set forth above. The structural
limitations of this claim would include approximately 800 different
nucleic acids, some of which would not be expected to work in view
of the state of the prior art. However, in view of the limited
number of possibilities and the expectation that there are at least
some, other than the specifically disclosed three, that would also
meet the functional limitation, it would be reasonable to conclude
that it would not require an undue amount of experimentation to
identify the nucleic acids encompassed by the claim.
Rejection:
Claims 1-3 are rejected under 35 U.S.C. § 112, first paragraph,
because the specification, while being enabling for an isolated
nucleic acid consisting of 10 to 35 nucleotides which hybridizes
preferentially to RNA or DNA of bacteria A and not to non-bacteria
A organisms, wherein said nucleic acid is or is complementary to
a nucleotide sequence consisting of at least ten consecutive nucleotides
from a nucleotide sequence selected from the group consisting of
SEQ ID NOS 1, 2, and 3, does not reasonably provide enablement
for any other embodiment encompassed by the claims. The specification
does not enable any person skilled in the art to which it pertains,
or with which it is most nearly connected, to identify or make
the invention commensurate in scope with these claims.
The specification discloses and the claims recite probes that
hybridize preferentially to RNA or DNA of bacteria A but not to
non-bacteria A organisms as well as methods of using the probes
to detect bacteria A. However, the state of the prior art as exemplified
by Wallace et al and Sambrook et al is such that determining the
specificity of hybridization probes is empirical by nature and
the effect of mismatches within an oligonucleotide probe is unpredictable.
Furthermore, a database search was done for 10mers of the three
specifically disclosed probes, the results of which are attached,
which suggest that some of the probes encompassed by the structural
limitations of the claims would not meet the functional limitation
thereof. The only working example given in the specification is
limited to the three specific sequences of SEQ ID NOS 1-3 and there
is no suggestion as to what the target sites in bacteria A are
or what modifications can be made while retaining the functional
limitation. In addition, claim 1 recites three limitations on the
nucleic acid, two structural and one functional. The two structural
limitation are 1) that the nucleic acid consists of 10 to 300 nucleotides
and 2) that the nucleic acid is or is complementary to a nucleotide
sequence comprising at least ten consecutive nucleotides
from a nucleotide sequence selected from the group consisting of
SEQ ID NOS 1, 2, and 3. Since the nucleotide sequence mentioned
merely comprises at least ten consecutive nucleotides from
a nucleotide sequence selected from the group consisting of SEQ
ID NOS 1, 2, and 3, it encompasses any random sequence of any length
as long as it has a stretch of at least ten consecutive nucleotides
that is the same as in SEQ ID NOS 1-3. Furthermore, since there
is no limitation that the claimed nucleic acid be complementary
to the nucleotide sequence at the stretch of at least ten consecutive
nucleotides that is the same as in SEQ ID NOS 1-3, the structural
limitations encompass any nucleic acid consisting of 10 to 300
nucleotides. Thus, claim 1 encompasses any nucleic acid that is
10 to 300 nucleotides in length and hybridizes preferentially to
RNA or DNA of bacteria A and not to non-bacteria A bacteria. Since
the structural limitations of the claim clearly covers any nucleic
acid that is 10 to 300 nucleotides in length (on the order of 4300
possible nucleic acids) and in view of the empirical and unpredictable
nature of the art and lack of guidance with respect to appropriate
modifications, one skilled in the art would have to make and test
all nucleic acids that meet the structural limitations to determine
which also meet the functional limitation. This amount of experimentation
would be impossible in many lifetimes. Therefore, based on the
empirical and unpredictable nature of the invention and state of
the prior art, the limited guidance and working examples in the
specification, and the extensive quantity of experimentation needed
to identify the nucleic acids encompassed by the claims, it would
require an undue amount of experimentation to identify or make
the nucleic acids encompassed by the claims.
If claim 1 was limited as follows, this rejection would be overcome:
1. An isolated nucleic acid consisting of 10 to 35 nucleotides
which hybridizes preferentially to RNA or DNA of bacteria A and
not to non-bacteria A organisms, wherein said nucleic acid is or
is complementary to a nucleotide sequence consisting of at least
ten consecutive nucleotides from a nucleotide sequence selected
from the group consisting of SEQ ID NOS 1, 2, and 3.
Example B: Hybridization Probes II
Specification: THE ONLY DIFFERENCE BETWEEN THE FACTS
IN EXAMPLE A AND THOSE OF EXAMPLE B IS THE LANGUAGE OF CLAIM
1. Specifically, the specification discloses that bacteria
A is known to cause a specific disease and, therefore, detection
of bacteria A in a sample is desirable. The specification even
discloses that methods are known which detect bacteria A in a
sample via culturing techniques. According to the specification,
such detection methods are difficult to perform and therefore
detection methods using nucleic acid probes are preferred.
The specification discloses that one object of the invention is
to provide nucleic acids complementary to unique nucleic acid sequences
within the RNA or DNA of bacteria A and which can be used to detect
bacteria A. Another object of the invention is to provide a method
of detecting bacteria A in a sample by contacting the sample with
a probe which preferentially hybridizes to RNA or DNA of bacteria
A but not to non-bacteria A organisms.
The term "probe" is described in the specification as a nucleic
acid between 10 and 300 base pairs in length which contain specific
nucleotide sequences that specifically and preferentially hybridize
under predetermined conditions to nucleic acid sequences of bacteria
A. The probes optionally contain a detectable moiety.
The following three specific probes were disclosed:
Bacteria A probe 1 (35mer) (SEQ ID NO:1)
5'-CATTAGAGTC GTACGTGCTA GACTGATTAA CCGGT-3'
Bacteria A probe 2 (33mer) (SEQ ID NO:2)
5'-CAATCCAGTA AGTTTTACCC GGCCAAATAA AGG-3'
Bacteria A probe 3 (30mer) (SEQ ID NO:3)
5'-AAATAGCCAG ATCATTGCCC CGGACCCTTG-3'
An example appears in the specification which demonstrates how
to carry out the detection and which shows that the three probes
are specific for bacteria A and fail to hybridize to 50 other types
of bacteria.
Claims:
- An isolated nucleic acid consisting of 10 to 300 nucleotides
wherein said nucleic acid is or is complementary to a nucleotide
sequence comprising any ten consecutive nucleotides from a nucleotide
sequence selected from the group consisting of SEQ ID NOS 1,
2, and 3.
- A probe comprising a nucleic acid of claim 1 and a detectable
moiety.
- A method of detecting the presence of bacteria A in a sample
suspected of containing bacteria A comprising
- a) contacting the sample with an isolated nucleic acid of
claim 1,
- b) imposing hybridization conditions on the sample and said
isolated nucleic acid to allow the formation of a hybridization
product between said nucleic acid and RNA or DNA from bacteria
A, if present in the sample, but not from RNA or DNA from non-bacteria
A bacteria; and
- c) detecting any hybridization product as an indication of
the presence of bacteria A in the sample.
State of the Prior Art: Same as in Example A. Specifically,
a search was carried out to compare the multitude of 10 nucleotide
probes encompassed by the claims with sequences in the EMBL database
with the following results:
- 10,541 database hits for the 10mers of probe 1;
- 15,378 database hits for the 10mers of probe 2;
- 5,691 database hits for the 10mers of probe 3.
Some of the hits for each probe were in the RNA or DNA of bacteria
other than bacteria A, such as Salmonella, Candida, and Streptococcus.
Wallace et al, Methods Enzymol. 152:432-443 (1987).
Sambrook et al, Molecular Cloning, A Laboratory Manual,
Second Edition, 1989, Cold Spring Harbor Laboratory, Cold Spring
Harbor, NY, p. 11.47.
Wallace et al and Sambrook et al teach the empirical nature of
determining the specificity of hybridization probes and the unpredictability
of the effect of mismatches within an oligonucleotide probe.
The 50 different bacteria tested within the example in the specification
are representative of bacteria in general.
Analysis:
There is a demonstration in the specification that the three specifically
disclosed probes can be used to detect bacteria A. Furthermore,
the sequences of those probes are disclosed so that one skilled
in the art could clearly make them. Therefore, the specification
does teach how to make and use three embodiments encompassed by
the claims. Accordingly, an objection/rejection using form paragraph
7.31.02 would be inappropriate. The issue is whether the enabled
embodiments are representative of the scope of the claims.
Before this can be determined, the scope of at least claim 1 must
be determined. Claim 1 recites two structural limitations for the
nucleic acid which are 1) that the nucleic acid consist of 10 to
300 nucleotides and 2) that the nucleic acid is or is complementary
to a nucleotide sequence comprising at least ten consecutive
nucleotides from a nucleotide sequence selected from the group
consisting of SEQ ID NOS 1, 2, and 3. Since the nucleotide sequence
mentioned merely comprises at least ten consecutive nucleotides
from a nucleotide sequence selected from the group consisting of
SEQ ID NOS 1, 2, and 3, it encompasses any random sequence of any
length as long as it has a stretch of at least ten consecutive
nucleotides that is the same as in SEQ ID NOS 1-3. Furthermore,
since there is no limitation that the claimed nucleic acid be complementary
to the nucleotide sequence at the stretch of at least ten consecutive
nucleotides that is the same as in SEQ ID NOS 1-3, claim 1 encompasses
any nucleic acid that is 10 to 300 nucleotides in length.
Since all nucleic acids within the scope of claim 1 could be clearly
identified and since nucleic acids can readily be synthesized by
those skilled in the art, one skilled in the art would know how
to identify and make all the nucleic acids encompassed by claim
1. However, does the specification teach how to use all nucleic
acids encompassed by claim 1? The answer in this case would be
no. The only disclosed use for the nucleic acids is in a method
of detecting the presence of bacteria A in a sample by preferentially
hybridizing to RNA or DNA of bacteria A but not to non-bacteria
A organisms, as in claim 3. The state of the prior art as exemplified
by Wallace et al and Sambrook et al is such that determining the
specificity of hybridization probes is empirical by nature and
the effect of mismatches within an oligonucleotide probe is unpredictable.
The database search results suggest that there are probes that
would meet the limitations of the claims but would not function
to detect bacteria A by preferentially hybridizing to RNA or DNA
of bacteria A but not to non-bacteria A organisms. The only specific
guidance or working example given in the specification is for the
three specific sequences of SEQ ID NOS 1-3 but there is no suggestion
as to what the target sites in bacteria A are or what modifications
can be made while retaining the ability to preferentially hybridize
to RNA or DNA of bacteria A. Therefore, based on these considerations,
it would be reasonable to conclude that it would require an undue
amount of experimentation to determine how to use all the nucleic
acids encompassed by the claims for detecting bacteria A in a sample.
In this case a scope rejection using form paragraph 7.31.03 would
be appropriate.
The only issue remaining is the decision as to the scope that
is enabled by the specification. Clearly the three probes used
in the example are enabled. Is this all that is enabled? The answering
of this question can be approached by considering claims having
narrower scope, but still having written descriptive support, and
determining whether the specification enables such a claim. Doing
this, a claim of the following scope would be enabled on the facts
presented here:
An isolated nucleic acid consisting of 10 to 35 nucleotides
which hybridizes preferentially to RNA or DNA of bacteria A and
not to non-bacteria A organisms, wherein said nucleic acid is
or is complementary to a nucleotide sequence consisting of at
least ten consecutive nucleotides from a nucleotide sequence
selected from the group consisting of SEQ ID NOS 1, 2, and 3.
Note, the insertion of the functional limitation, i.e., that the
nucleic acid must hybridize preferentially to RNA or DNA or bacteria
A and not to non-bacteria A organisms, by itself would be such
that the disclosure would enable the use of those nucleic acids
encompassed by the claim. However, there would still be enablement
problems, as seen in Example A, requiring further structural limitations.
The upper limit of 35 nucleotides has clear descriptive support
based on the fact that one of the specific probes of the example
has 35 nucleotides. Nothing larger than 35, other than 300, has
specific descriptive support and an upper limit of 300 would not
be enabled for the reasons set forth above and in Example A. The
structural limitations of this claim would include approximately
800 different nucleic acids, some of which would not be expected
to work in view of the state of the prior art. However, in view
of the limited number of possibilities and the expectation that
there are at least some, other than the specifically disclosed
three, that would also meet the functional limitation, it would
be reasonable to conclude that it would not require an undue amount
of experimentation to identify and use the nucleic acids encompassed
by the claim.
Rejection:
Claims 1-3 are rejected under 35 U.S.C. § 112, first paragraph,
because the specification, while being enabling for the exact probes
represented by SEQ ID NOS 1-3 and 10mers to 35mers thereof that
preferentially hybridize to RNA or DNA of bacteria A and not to
non-bacteria A organisms, does not reasonably provide enablement
for any other embodiment encompassed by the claims. The specification
does not enable any person skilled in the art to which it pertains,
or with which it is most nearly connected, to use the invention
commensurate in scope with these claims.
The specification discloses and the claims recite probes having
10 to 300 nucleotides as well as methods of using the probes to
detect bacteria A. However, the state of the prior art as exemplified
by Wallace et al and Sambrook et al is such that determining the
specificity of hybridization probes is empirical by nature and
the effect of mismatches within an oligonucleotide probe is unpredictable.
Furthermore, a database search was done for 10mers of the three
specifically disclosed probes, the results of which are attached,
which suggest that some of the probes encompassed by the claims
would not preferentially hybridize to RNA or DNA of bacteria A
and not to non-bacteria A organisms so as to detect bacteria A.
The only working example given in the specification is limited
to the three specific sequences of SEQ ID NOS 1-3 and there is
no suggestion as to what the target sites in bacteria A are or
what modifications can be made to the sequences or the hybridization
conditions while retaining the ability to detect bacteria A. In
addition, claim 1 recites two limitations on the nucleic acids,
both structural. The two structural limitations are 1) that the
nucleic acid consists of 10 to 300 nucleotides and 2) that the
nucleic acid is or is complementary to a nucleotide sequence comprising at
least ten consecutive nucleotides from a nucleotide sequence selected
from the group consisting of SEQ ID NOS 1, 2, and 3. Since the
nucleotide sequence mentioned merely comprises at least
ten consecutive nucleotides from a nucleotide sequence selected
from the group consisting of SEQ ID NOS 1, 2, and 3, it encompasses
any random sequence of any length as long as it has a stretch of
at least ten consecutive nucleotides that is the same as in SEQ
ID NOS 1-3. Furthermore, since there is no limitation that the
claimed nucleic acid be complementary to the nucleotide sequence
at the stretch of at least ten consecutive nucleotides that is
the same as in SEQ ID NOS 1-3, claim 1 encompasses any nucleic
acid that is 10 to 300 nucleotides in length (on the order of 4300
possible nucleic acids). In view of this, the empirical and unpredictable
nature of the art, the lack of guidance with respect to appropriate
modifications and the lack of guidance as to how to use other probes
within the scope of the claims to detect bacteria A, the specification
does not teach one skilled in the art how to successfully use probes
of the claimed scope without undue experimentation.
If claim 1 was limited as follows, this rejection would be overcome:
1. An isolated nucleic acid consisting of 10 to 35 nucleotides
which hybridizes preferentially to RNA or DNA of bacteria A and
not to non-bacteria A organisms, wherein said nucleic acid is or
is complementary to a nucleotide sequence consisting of at least
ten consecutive nucleotides from a nucleotide sequence selected
from the group consisting of SEQ ID NOS 1, 2, and 3.
Example C: Chemical Reagents I
Specification: The specification discloses that prothrombin
is essential to the blood coagulation cascade and that a deficiency
in prothrombin in blood leads to the hemorrhagic disease known
as congenital hypoprothrombinemia. Thus, the object of the invention,
as set forth in the specification, is to provide a method and reagent
for detecting prothrombin in blood, wherein the method can be used
in the diagnosis of congenital hypoprothrombinemia. If the results
of the method indicate that prothrombin is present in normal amounts
in the patient's blood sample then congenital hypoprothrombinemia
is ruled out, whereas if the results of the method indicate that
the patient's blood is deficient in prothrombin then the patient
is diagnosed as having congenital hypoprothrombinemia and is treated
accordingly. The specification discloses that treatments for that
condition are well known in the art. The normal range for prothrombin
in blood is also well known in the art and is listed in the specification.
The specification discloses that when the well known material compound
X is added to whole blood, it reacts with prothrombin to produce
an absorbance change when measured at 280nm. However, the specification
discloses that fibrinogen in blood also reacted with compound X
to interfere with the results. To overcome this, the specification
discloses adding boric acid to the blood along with compound X.
The boric acid complexes with the fibrinogen to inhibit any reaction
of the fibrinogen and compound X so that any absorbance change
would be due solely to prothrombin. The specification includes
a general statement that any other compound which inhibits the
reaction of fibrinogen with compound X can be used in place of
the boric acid but nothing other than boric acid is specifically
named and no guidance is provided as to how or why the boric acid
complexes with fibrinogen to inhibit its reaction with compound
X. The specification discloses appropriate concentration ranges
for compound X and boric acid as well as the appropriate mixing
ratios for the reagent and sample but states that the ranges and
ratios are not critical. The sole example in the specification
carries out the method by adding a predetermined amount of the
reagent to a whole blood sample, measuring the absorbance of the
whole blood sample at 280nm before and after the addition of the
reagent, calculating the difference between the absorbance of the
whole blood sample before and after the addition of the reagent,
and determining the amount of prothrombin in the sample from the
difference. The example uses a reagent containing compound X and
boric acid in specific amounts. The example also demonstrates how
to establish the appropriate calibration curve.
Claims:
- A reagent for measuring the amount of prothrombin in whole
blood comprising compound X and a substance which inhibits any
reaction between fibrinogen and compound X.
- A method for measuring the amount of prothrombin in whole blood
comprising:
adding a predetermined amount of the reagent of claim 1 to a
whole blood sample;
measuring the absorbance of the whole blood sample at 280nm before
and after the addition of the reagent;
calculating the difference between the absorbance of the whole
blood sample before and after the addition of the reagent; and
determining the amount of prothrombin in the sample from the
difference.
- 3. A reagent according to claim 1 wherein the substance is
boric acid.
State of the Prior Art: No compounds which inhibit any
reaction between fibrinogen and compound X are known.
Analysis:
There is a demonstration that one reagent, i.e., one that contains
compound X and boric acid, can be used to detect prothrombin. Furthermore,
since compound X and boric acid are well known materials, one skilled
in the art could clearly make them without undue experimentation.
Therefore, the specification does teach how to make and use one
embodiment encompassed by the claims, particularly the embodiment
recited in claim 3. Accordingly, an objection/rejection using form
paragraph 7.31.02 would be inappropriate. The issue is whether
the enabled embodiment is representative of the scope of the claims.
Based on the undue experimentation factors, particularly the breadth
of the claims and the lack of guidance as to other materials which
inhibit any reaction between compound X and fibrinogen, the conclusion
would be that the enabled embodiment is not representative of the
scope of claims 1-2. Therefore, a scope rejection using form paragraph
7.31.03 would be appropriate against claims 1-2.
Rejection:
Claims 1-2 are rejected under 35 U.S.C. § 112, first paragraph,
because the specification, while being enabling for a reagent that
includes compound X and boric acid, does not reasonably provide
enablement for reagents that include compound X and any substance
which inhibits any reaction between fibrinogen and compound X.
The specification does not enable any person skilled in the art
to which it pertains, or with which it is most nearly connected,
to make the invention commensurate in scope with these claims.
The claims recite a reagent and a method of using the reagent
to detect prothrombin wherein the reagent includes a substance
which inhibits any reaction between compound X and fibrinogen.
This encompasses any substance which has that ability. However,
the specification only teaches the use of boric acid as the inhibitor.
The specification does not provide guidance as to any other substances
which have that ability nor does the specification disclose specific
characteristics for such substances. Furthermore, the specification
fails to provide guidance as to how or why the boric acid complexes
with fibrinogen to inhibit its reaction with compound X. Without
such information, one skilled in the art could not predict which
substances out of the vast numbers of known substances would react
with fibrinogen in a manner similar to boric acid and, accordingly,
one skilled in the art would be required to perform undue experimentation
to identify any other compounds that would complex with fibrinogen
so as to inhibit its reaction with compound X. Therefore, one skilled
in the art could not make the invention without undue experimentation.
Modifications to the Above Facts: Let us assume that the
above noted application was filed on January 11, 1994. Subsequent
to that date, two articles were published in Nature, one on March
26, 1995 and one on October 10, 1995, each of which discloses five
different compounds which inhibit any reaction between fibrinogen
and compound X. Another original application, identical to the
above application, is filed on July 20, 1996. Does the enablement
analysis above change with respect to this later filed application?
Clearly the answer is yes. Since the specification suggests the
use of compounds other than boric acid, such other compounds are
well known in the prior art as exemplified by the two articles,
and the specification need not disclose what is well known in the
art, and preferably omits it, all of the claims in the July 20,
1996 application would be enabled.
Example D: Chemical Reagents II
Specification: THE MAJOR DIFFERENCES BETWEEN THE FACTS OF EXAMPLE
C AND THOSE OF EXAMPLE D ARE: 1) IN EXAMPLE C, BORIC ACID IS
DISCLOSED AS THE INHIBITOR SUBSTANCE WHEREAS NO SPECIFIC INHIBITOR
SUBSTANCE IS DISCLOSED IN EXAMPLE D; THERE ARE NO WORKING EXAMPLES
IN EXAMPLE D; AND 3) EXAMPLE C HAS THREE CLAIMS WHEREAS EXAMPLE
D HAS TWO CLAIMS.
Specifically, the specification discloses that prothrombin is
essential to the blood coagulation cascade and that a deficiency
in prothrombin in blood leads to the hemorrhagic disease known
as congenital hypoprothrombinemia. Thus, the object of the invention,
as set forth in the specification, is to provide a method and reagent
for detecting prothrombin in blood, wherein the method can be used
in the diagnosis of congenital hypoprothrombinemia. If the results
of the method indicate that prothrombin is present in normal amounts
in the patient's blood sample then congenital hypoprothrombinemia
is ruled out, whereas if the results of the method indicate that
the patient's blood is deficient in prothrombin then the patient
is diagnosed as having congenital hypoprothrombinemia and is treated
accordingly. The specification discloses that treatments for that
condition are well known in the art. The normal range for prothrombin
in blood is also well known in the art and is listed in the specification.
The specification discloses that when the well known material compound
X is added to whole blood, it reacts with prothrombin to produce
an absorbance change when measured at 280nm. However, the specification
discloses that fibrinogen in blood also reacts with compound X
to interfere with the results. To overcome this, the specification
discloses adding an inhibitor substance to the blood along with
compound X. The inhibitor substance is to complex with the fibrinogen
to inhibit any reaction of the fibrinogen and compound X so that
an absorbance change would be due solely to prothrombin. The specification
includes a general statement that any compound which inhibits the
reaction of fibrinogen with compound X can be used. However, not
one specific inhibitor is mentioned in the specification. The specification
discloses appropriate concentration ranges for compound X as well
as the appropriate mixing ratios for the reagent and sample but
states that the ranges and ratios are not critical. There is no
working example but the specification does clearly disclose that
the method would be carried out by adding a predetermined amount
of the reagent to a whole blood sample, measuring the absorbance
of the whole blood sample at 280nm before and after the addition
of the reagent, calculating the difference between the absorbance
of the whole blood sample before and after the addition of the
reagent, and determining the amount of prothrombin in the sample
from the difference.
Claims:
- A reagent for measuring the amount of prothrombin in whole
blood comprising compound X and a substance which inhibits any
reaction between fibrinogen and compound X.
- A method for measuring the amount of prothrombin in whole blood
comprising:
adding a predetermined amount of the reagent of claim 1 to a
whole blood sample;
measuring the absorbance of the whole blood sample at 280nm before
and after the addition of the reagent;
calculating the difference between the absorbance of the whole
blood sample before and after the addition of the reagent; and
determining the amount of prothrombin in the sample from the
difference.
State of the Prior Art: No compounds which inhibit any
reaction between fibrinogen and compound X are known.
Analysis:
The claims require a substance which inhibits any reaction between
compound X and fibrinogen. However, the specification fails to
disclose any specific substance that has that ability and there
is no working example to provide this missing information. Therefore,
based on the undue experimentation factors, particularly the breadth
of the claims, the lack of guidance as to materials which inhibit
any reaction between compound X and fibrinogen, and the lack of
working examples, the conclusion would be that the specification
does not teach how to make and use even one embodiment encompassed
by the claims. Accordingly, an objection/rejection using form paragraph
7.31.02 would be appropriate.
Rejection:
Claims 1-2 are rejected under 35 U.S.C. § 112, first paragraph,
because the specification does not enable any person skilled in
the art to which it pertains, or with which it is most nearly connected,
to make the invention.
The claims recite a reagent and a method of using the reagent
to detect prothrombin wherein the reagent includes a substance
which inhibits any reaction between compound X and fibrinogen.
This encompasses any substance which has that ability. However,
the specification does not provide guidance as to any specific
substances which have that ability nor does the specification disclose
specific characteristics for such substances. Furthermore, the
specification fails to provide guidance as to how any inhibitor
substance should complex with fibrinogen to inhibit its reaction
with compound X. No working examples are provided to provide such
missing information. Without such information, one skilled in the
art could not predict which substances out of the vast numbers
of known substances would react with fibrinogen in the manner required
by the method and, accordingly, one skilled in the art would be
required to perform undue experimentation to identify any compounds
that would complex with fibrinogen so as to inhibit its reaction
with compound X. Therefore, one skilled in the art could not make
the invention without undue experimentation.
Example 5E: Peptides for Treating Obesity
Specification: The specification discloses an anti-obesity
peptide having the following amino acid sequence:
1 5 10 15
Phe Ile Gly His Thr Ser Xaa Thr His Glu Xaa Phe Ala Thr Xaa Trp
Glu Leu Leu (SEQ ID NO 1).
Where:
Xaa at position 7 is Gln, Ile, or Met;
Xaa at position 11 is Asp, Gln, or Glu; and
Xaa at position 15 is Ser or Pro.
Preferably,
Xaa at position 7 is Ile;
Xaa at position 11 is Glu; and
Xaa at position 15 is Ser.
The specification also discloses a pharmaceutical formulation
comprising the peptide of SEQ ID NO 1 and a pharmaceutically acceptable
carrier, diluent, and/or excipient, as well as a method of treating
obesity by administering the peptide of SEQ ID NO 1 to an obese
mammal, such as mice or humans. Several routes of administration
are disclosed but no dosages, not even general ranges, are disclosed.
The specification states that the peptide can be made by recombinant
DNA technology or well known peptide synthesis procedures. Furthermore,
the specification lists DNA sequences, vectors, host cells, and
isolation techniques suitable for producing the peptide by recombinant
DNA technology as well as specific peptide synthesis techniques
suitable for producing the peptide.
The application discloses but does not exemplify that the peptide
is a fragment of a larger protein produced in adipose tissue. The
application also discloses but does not exemplify that the peptide
is able to control body weight gain in normal and obese subjects.
The specification discloses that suitable test animals include
normal mice and obese mice, especially the ob/ob mouse model of
obesity and diabetes, which is disclosed as being generally accepted
in the art as being indicative of the obesity condition. The specification
discloses how to carry out the animal model tests but fails to
disclose whether such tests were done using the peptide of the
invention. The specification also goes on to state that the peptide
is also useful in the production of antibodies for diagnostic use
and, as a peptide, is useful as feed additives for animals.
Claims:
- 1. A peptide consisting of the sequence
1 5 10 15
Phe Ile Gly His Thr Ser Xaa Thr His Glu Xaa Phe Ala Thr Xaa
Trp Glu Leu Leu (SEQ ID No. 1), wherein
Xaa at position 7 is Gln, Ile, or Met;
Xaa at position 11 is Asp, Gln, or Glu; and
Xaa at position 15 is Ser or Pro.
- The peptide of claim 1 wherein Xaa at position 7 is Ile; Xaa
at position 11 is Glu; and Xaa at position 15 is Ser.
- A pharmaceutical composition comprising the peptide of claim
1 and a pharmaceutically acceptable carrier.
- A pharmaceutical composition comprising the peptide of claim
2 and a pharmaceutically acceptable carrier.
- A method of treating obesity, which comprises administering
to a mammal in need thereof the peptide of claim 1.
- A method of treating obesity, which comprises administering
to a mammal in need thereof the peptide of claim 2.
State of the Prior Art: There are no structurally similar
peptides known in the art for treating obesity. There are other
proteins that the art suggests play a role in obesity. The following
references establish the state of the art with respect to such
proteins.
Zhang et al, Nature, Vol. 372, pp. 425-432, December 1994.
Rink, Nature, Vol. 372, pp. 406-407, December 1994.
Marx, Science, Vol. 266, pp. 1477-1478, December 1994.
It is well established in the art how to use proteins and peptides
as additives in animal feed.
Analysis:
The specification clearly teaches how to make all the peptides
and compositions encompassed by the claims. Therefore, "how to
make" is not an issue with any of the claims.
With respect to claims 1-2, the fact that the specification discloses
that the peptides can be used as an additive to animal feed in
combination with the fact that it is well established in the art
how to use proteins and peptides as additives in animal feed leads
to a conclusion that the specification also teaches how to use
the entire scope of peptides recited in claims 1-2. Since no specific
use is recited in these claims, one enabled use that covers the
full scope of the claims is sufficient to preclude an enablement
rejection of a compound claim based on the failure to teach "how
to use".
With respect to claims 3-4, the "pharmaceutical" and "pharmaceutically
acceptable carrier" language in combination with the fact that
the only disclosed pharmaceutical use of the compositions is for
treating obesity leads to the conclusion that these claims should
be evaluated in terms of whether the specification teaches how
to use the compositions for treating obesity. Since method claims
5-6 must be evaluated in terms of the recited use, treating obesity,
claims 3-6 should be evaluated together. In this case, the art
noted above teaches that few medical problems have proved to be
more intractable than obesity (Marx). Furthermore, even though
other proteins are suggested as playing a role in obesity (Zhang),
the art, such as Rink and Marx, suggest that it is not even known
how to use these proteins for treating obesity. This state of the
prior art suggests a lack of predictability in this art which,
taken with the fact that there is a lack of guidance with respect
to dosages and a lack of working examples, leads to the conclusion
that it would require undue experimentation to use the invention
of claims 3-6. With respect to claims 3-4, it is also noted that
if the "pharmaceutical" and "pharmaceutically acceptable" language
was deleted from the claims, the analysis would be the same as
that set forth above with respect to claims 1-2. Therefore, an
enablement rejection using form paragraph 7.31.02 of claims 3-6
would be appropriate along with a suggestion to remove the "pharmaceutical" and "pharmaceutically
acceptable" language from claims 3-4 to overcome the rejection
with respect to these claims.
Rejection:
Claims 3-6 are rejected under 35 U.S.C. § 112, first paragraph,
because the specification does not enable any person skilled in
the art to which it pertain, or with which it is most nearly connected,
to use the invention.
Claims 3-6 recite pharmaceutical compositions and methods of treating
obesity using certain specific peptides. However, the specification
fails to disclose any dosages for use in treating obesity. Furthermore,
while the specification sets forth tests for assay anti-obesity
activity of the peptides, the specification fails to provide any
indication that such tests were done. Therefore, the specification
also fails to provide any working examples. Marx states that few "medical
problems have proved to be more intractable than obesity" and even
though other proteins are suggested as playing a role in obesity
(Zhang), the art, such as Rink and Marx, suggest that it is not
even known how to use these proteins for treating obesity and that
there is much more to be done before obesity can be treated using
such proteins. In view of the intractable nature and unpredictability
of treating obesity and the lack of guidance with respect to dosages
and the lack of working examples, one skilled in the art could
not use the inventions of claims 3-6 without undue experimentation.
Note, removing "pharmaceutical" and "pharmaceutically acceptable" from
claims 3-4 would overcome the rejection of these claims since one
would know how to use such compositions as additives in animal
feed as disclosed in the specification.
Modifications to the Above Facts: Let us assume that in
addition to the above facts, the specification actually stated "The
disclosed animal model assays were carried out using the peptides
of the invention and the peptides were active in at least one of
the assays. Therefore, the peptides are useful in treating obesity
and those disorders implicated by obesity." Does this change the
analysis set forth above? For claims 1-2, the answer is no. For
claims 3-6, the answer is yes. Specifically, if the assays are
reasonably correlative to treatment in other mammals such a statement
would constitute the presence of working examples, even without
the specific data. In this case, since specific dosages are not
disclosed generally or in the examples, the only issue remaining
is whether it would require an undue amount of experimentation
to determine the proper dosages based on the examples and the state
of the prior art and any enablement rejection must address this
issue. If the assays do not reasonably correlate to treatment in
other mammals based on the state of the art, this issue would have
to be raised along with the other issues noted in the analysis
and rejection above.
Note, taking the position that the assays are reasonably correlative
to treatment in other mammals, it is proper to accept as being
true the statement that the peptides were active in the assays,
even in the absence of specific data. The Office must accept as
being true the statements supporting enablement unless there is
an objective reason, usually supported with documentary evidence,
to question them, i.e., the burden is on the Office to demonstrate
that there is an objective reason, usually supported by documentary
evidence, to question the statement. Here, there is no evidence
indicating that the peptides were not active in the assays. However,
this analysis does not necessarily apply to other issues, such
as a showing of unexpected results so as to overcome a rejection
under 35 U.S.C. 103. In that case, a statement that the assays
demonstrated unexpected results for the inventive peptides, in
the absence of the specific results, would not be persuasive since
it is applicant's burden to rebut the prima facie case of obviousness
and the Office cannot determine whether applicant has met that
burden without the results being present.
Example F: Enablement and Prior Art Rejections
Specification: Compounds of the formula I or a pharmaceutically
acceptable salt thereof are disclosed:
I wherein R1 is C1 - C10 alkyl; R2 and R3 are independently hydrogen,
methyl, methoxy, fluoro, chloro, bromo, or trifluoromethyl;
![Chemical Structure 1](images/i1.gif)
Z is
![Chemical Structure 2](images/i2.gif)
or
![Chemical Structure 3](images/i3.gif)
; and Het is an heteroaromatic group.
The compounds are said to possess efficacy in treating a wide
range of tumors in mammals. No antitumor data (in vitro or in
vivo) are presented in the specification. The tumor types are
merely listed and include estrogen-dependent tumors such as breast
cancer. Detailed methods of synthesizing the compounds are disclosed.
Claim:
1. A method of treating tumors in mammals which comprises administering
to a mammal in need thereof an antitumor effective amount of the
compound of formula I or a pharmaceutically acceptable salt thereof.
State of the Prior Art: The following references are representative
of the state of the prior art:
U.S. Patent No. 4,605,661
U.S. Patent No. 4,916,144
These two patents disclose compounds which are effective against
estrogen dependent tumors and which are stucturally similar to
some of the compounds recited in claim 1.
Internal Medicine, 4th Edition, Editor-in-Chief Jay Stein, Chapters
71-72, pages 699-715. This reference provides evidence that the
various types of cancers have different causative agents, involve
different cellular mechanisms, and, consequently, differ in treatment
protocol.
Situation 1 - Proper §112, ¶1 and §103 rejections in the same
Office action:
Claim 1 is rejected under 35 U.S.C. 112, first paragraph because
the specification, while being enabling for treatment of estrogen
dependent tumors with compounds of formula I wherein Het is imidazolyl,
does not reasonably provide enablement for treatment of tumors
generally with all of the compounds of the claim. The specification
does not enable any person skilled in the art to which it pertains,
or with which it is most nearly connected, to use the invention
commensurate in scope with claim 1.
The cancer therapy art remains highly unpredictable, and no example
exists for efficacy of a single product against tumors generally.
Specifically, Internal Medicine, 4th Edition, Editor-in-Chief Jay
Stein, Chapters 71-72, pages 699-715, teaches that the various
types of cancers have different causative agents, involve different
cellular mechanisms, and, consequently, differ in treatment protocol.
It is also known that certain tumors are dependent upon estrogen
for their induction or stimulation (e.g. breast tumors) and others
are not. See USPs 4605661 and 4916144. Based on this state of the
art, an estrogen inhibitor would be expected to be effective against
those that are dependent upon estrogen for their induction, but
not against those that do not depend upon estrogen for their induction.
Since, the compounds used in claim 1 are structurally related to
compounds known to be effective against estrogen dependent tumors
(again see USPs 4605661 and 4916144), one skilled in the art would
expect the compounds used in claim 1 in which Het is imidazolyl
to have similar activity and, accordingly, would know how to make
and use these compounds for treating estrogen dependent tumors.
However, when Het is not imidazolyl, the compounds would not be
expected to be estrogen inhibitors due to stuctural differences.
Furthermore, applicant has provided no guidance or working examples
teaching one skilled in the art how to determine which of the countless
products used in claim 1 would be effective against which tumors.
As evidenced by the references noted above, one would not expect
all of the compounds of formula I to be effective against all tumors.
Therefore, based on the unpredictable nature of the invention and
state of the prior art, the lack of guidance and working examples,
and the extreme breadth of the claims, one skilled in the art could
not use the entire scope of the claimed invention without undue
experimentation.
Claim 1 is rejected under 35 U.S.C. 103 as obvious over Hirsch
et al (USP 4605661). Hirsch et al discloses (see example 3 at column
4)
![Chemical Structure 4](images/i4.gif)
which differs from a compound within instant formula I by hydrogen
vs. alkyl substitution at position 2. The reference compound inhibits
aromatase and is useful for treating breast cancer. See Table I
at top of column 5. It would have been obvious to one of ordinary
skill in the art at the time the invention was made to substitute
a methyl group for hydrogen in the reference compound. One would
have been motivated to make the substitution because of the close
structural relationship of the two compounds (ethyl and isopropyl
are homologs) and because one of ordinary skill in the art would
have reasonably expected that such substitution would produce an
aromatase inhibitor useful for treating breast cancer in view of
that close structural relationship.
Situation 2 - Improper §112, ¶1 and §103 rejections in the same
Office action:
Claim 1 is rejected under 35 U.S.C. 112, first paragraph because
the specification does not enable any person skilled in the art
to which it pertains, or with which it is most nearly connected,
to use the invention.
The cancer therapy art remains highly unpredictable, and no example
exists for efficacy of a single product against tumors generally.
Specifically, Internal Medicine, 4th Edition, Editor-in-Chief Jay
Stein, Chapters 71-72, pages 699-715, teaches that the various
types of cancers have different causative agents, involve different
cellular mechanisms, and, consequently, differ in treatment protocol.
Furthermore, applicant has provided no guidance or working examples
teaching one skilled in the art how to determine which of the countless
products used in claim 1 would be effective against which tumors.
As evidenced by the reference noted above, one would not expect
all of the compounds of formula I to be effective against all tumors.
Therefore, based on the unpredictable nature of the invention and
state of the prior art, the lack of guidance and working examples,
and the extreme breadth of the claims, one skilled in the art could
not use the claimed invention without undue experimentation.
Claim 1 is rejected under 35 U.S.C. 103 as obvious over Hirsch
et al (USP 4605661). Hirsch et al discloses (see example 3 at column
4)
![Chemical Structure 4](images/i4.gif)
which differs from a compound within instant formula I by hydrogen
vs. alkyl substitution at position 2. The reference compound inhibits
aromatase and is useful for treating breast cancer. See Table I
at top of column 5. It would have been obvious to one of ordinary
skill in the art at the time the invention was made to substitute
a methyl group for hydrogen in the reference compound. One would
have been motivated to make the substitution because of the close
structural relationship of the two compounds (ethyl and isopropyl
are homologs) and because one of ordinary skill in the art would
have reasonably expected that such substitution would produce an
aromatase inhibitor useful for treating breast cancer in view of
that close structural relationship.
Analysis:
Based on the state of the prior art considered with the disclosure,
some of the compounds within the claimed genus (or close structural
analogs thereof) are useful for treating estrogen-dependent tumors.
There is no reason to question enablement for those compounds because
of their structural similarity to known compounds which have the
same use, i.e., treating estrogen-dependent tumors. Accordingly,
the scope rejection in situation 1 is appropriate. Since something
is clearly enabled for these reasons, the enablement rejection
in situation 2, which states that nothing is enabled, is inappropriate.
The obviousness rejection is appropriate in both situations because
certain compounds within the disclosed genus would have been obvious
for the reference use (which also happens to be the instant utility).
Since both rejections are appropriate in situation 1, making both
rejections would be proper. However, in situation 2, the combination
of rejections is inconsistent because it implies that one skilled
in the art would be able to make the claimed analogs of the prior
art and know how to use them (the §103 rejection), but at the same
time would not know how to use any of the compounds
of the instant invention (the §112 rejection). This is not proper
given the facts of this case.
Modification of the Above Facts: Let us assume now that
the specification did not list any tumor types for which the compounds
possess efficacy. Does this change the analysis set forth above?
The answer is no. In this case, situation 1 would still be appropriate.
However, applicant should also be put on notice that the enabled
embodiment lacks explicit written descriptive support in the specification
as filed.
Example G: Gene Therapy
Specification: The specification discloses that viruses are
commonly used as vectors to introduce genes into cells by first inserting
the gene of interest into the DNA of the virus and then contacting
the virus with the cells. The virus then infects the cells through
cell binding receptors on the surface of the virus which bind to
the cells and cause the virus to be internalized by the cells. Once
internalized, the virus inserts its DNA, including the gene of interest,
into the genome of the cell in such a manner that the gene of interest
is expressed so as to produce its corresponding protein. Applicant
has discovered that if viral vectors are first contacted with the
recently discovered protein algernin, the algernin complexes with
the cell binding receptors on the surface of the virus, changes the
conformation thereof, and increases the infectivity of the viral
vector by a factor of ten. Thus, the invention relates to a complex
between a viral vector and algernin and is applicable to all situations
where it is desirable to introduce genes into mammalian cells with
a viral vector with a higher than normal rate of infectivity. Specifically,
the specification discloses that the modified viral vector can be
used in vitro for providing desired biological action in the
cells, e.g., to produce useful proteins, and, when combined with
a pharmaceutically acceptable carrier in a pharmaceutical composition, in
vivo for medicinal purposes, such as gene therapy.
The specification lists several examples of viral vectors which
are candidates for use within the claimed invention. The specification
also provides the amino acid sequence of algernin as well as various
methods of obtaining algernin suitable for use in the invention.
The specification includes several in vitro working examples
with representative samples of viral vectors, genes of interest,
and cells demonstrating that when the viral vectors are complexed
with algernin, the complex shows a higher rate of infectivity.
The examples further demonstrate that the gene of interest in the
infected cells is then expressed so as to produce its corresponding
protein. The specification does not show any examples relating
to gene therapy or any in vivo use of the viral vectors.
Claims:
- A viral vector comprising:
a virus comprising a cell binding receptor on the surface thereof
and a gene of interest, not normally present in the virus, inserted
within the DNA of the virus; and
algernin complexed to the cell binding receptor of the virus.
- A pharmaceutical composition comprising a therapeutically effective
amount of the complex of claim 1 and a pharmaceutically acceptable
carrier.
- A method for introducing a gene of interest into a cell comprising
contacting said cell with the viral vector of claim 1.
State of the Prior Art: The state of the prior art is such
that using viral vectors to insert genes into cells in vitro is
well known and is used in applications such as protein production
and as a research tool.
Orkin et al., December 7, 1995, "Report and Recommendation of
the Panel to Assess the NIH Investmen in Research on Gene Therapy",
issued by the National Institutes of Health - This reference teaches
that using viral vectors to insert genes into cells in vivo for
therapeutic purposes, i.e., gene therapy, is highly unpredictable
and undeveloped in view of the complexity of in vivo systems.
Analysis:
The specification discloses an in vitro use for the viral
vector of claim 1 and clearly discloses how to make and use the viral
vector in the in vitro environment. Since claim 1 does not
recite any environment of use, only one enabled use covering the
scope of the claim is needed to enable the claim. Therefore, the
disclosure with respect to the in vitro use of the viral vector
is sufficient to enable claim 1 and it would be inappropriate to
include claim 1 in a rejection under 35 U.S.C. 112, first paragraph.
With respect to claim 2, the "pharmaceutical composition", "therapeutically
effective", and "pharmaceutically acceptable carrier" language
in combination with the fact that the only disclosed pharmaceutical
use of the compositions is for gene therapy leads to the conclusion
that this claim should be evaluated in terms of whether the specification
teaches how to make and use the composition for gene therapy. Since
the specification fails to provide any guidance regarding gene
therapy, such as dosages, routes of administration, and working
examples, and the state of the prior art is such that gene therapy
is unpredictable and undeveloped, it would be reasonable to conclude
that it would require an undue amount of experimentation to determine
the therapeutically effective amounts and use the compositions
for gene therapy. For the reasons set forth above with respect
to claim 1, it is clear that non-therapeutic compositions would
be enabled. Since some compositions are enabled, it would be best
to make a scope rejection of claim 2 using form paragraph 7.31.03.
Claim 3 is a broad claim. When read in light of the specification,
it covers in vitro applications as well as in vivo gene
therapy applications. Thus, claim 3 must be evaluated as to whether
the specification enables the entire scope of the claim. From the
above discussion with respect to claims 1 and 2, it is clear that
the specification enables the in vitro aspects of the claim
but not the in vivo gene therapy aspects of the claim. Therefore,
it would be reasonable to make a scope rejection of claim 3 using
form paragraph 7.31.03.
Rejection:
Claims 2-3 are rejected under 35 U.S.C. 112, first paragraph, because
the specification, while enabled for non-therapeutic compositions
and in vitro uses of the viral vector of the invention, does
not reasonably provide enablement for pharmaceutical compositions
and their use in vivo for gene therapy. The specification
does not enable any person skilled in the art to which it pertains,
or with which it is most nearly connected, to make and use the invention
commensurate in scope with these claims.
Claim 2 is directed to a pharmaceutical composition comprising
a specific viral vector, the only disclosed use of the composition
being in vivo gene therapy. Claim 3 is directed to a method
which encompasses of using the specific viral vector for in
vivo gene therapy. However, the specification fails to adequately
teach how to make the composition having a "therapeutically effective
amount" of the viral vector and how to use the composition and
vector for in vivo gene therapy. Gene therapy is a highly
unpredictable and undeveloped field and the skill in the art is
high. See Orkin et al. which states:
2. While the expectations and the promise of gene therapy
are great, clinical efficacy has not be definitively demonstrated
at this time in any gene therapy protocol, despite anecdotal claims
of successful therapy and the initiation of more than 100 Recombinant
DNA Advisory Committee (RAC)-approved protocols.
3. Significant problems remain in all basic aspects of gene therapy.
The specification fails to disclose the intended patients, amounts
of the viral vector to be administered, what amount is considered
to be therapeutically effective, the route and time course of administration,
the sites of administration, the intended therapeutic product,
the intended disease, and the intended target organs. The specification
also lacks any working examples showing that the viral vector as
claimed would deliver the genes encoding the therapeutic products
to the appropriate site and that the genes once delivered would
be expressed sufficiently to provide adequate product to effect
the desired therapy. In view of the quantity of experimentation
necessary to determine the above parameters, the lack of direction
or guidance presented, the absence of working examples for in
vivo gene therapy, the breadth of the claims, and the unpredictable
and undeveloped state of the art with respect to gene therapy,
it would require undue experimentation for one skilled in the art
to practice the entire scope of the claimed invention.
If claims 2 and 3 were limited as follows, this rejection would
be overcome:
2. A composition comprising the viral vector of claim 1 and a carrier.
3. A method for introducing a gene of interest into a cell in
vitro comprising contacting said cell with the viral vector
of claim 1.
Example H: Endothelin Receptor Antagonists
Specification: The specification discloses compounds of formula
![Chemical Structure 5](images/i5.gif)
wherein HET is a 5- or 6-membered heterocyclic ring containing
at least one hetero atom selected from N, S and O, such as morpholinyl,
piperazinyl, piperidinyl, pyrazinyl, pyrimidinyl, oxadiazolyl,
thiadiazolyl, oxazolyl, and thiazolyl, wherein HET can be optionally
substituted with X; X is hydrogen, lower alkyl, lower alkoxy, hydroxy,
halo, lower monoalkylamino, lower dialkylamino, nitro, cyano, acylamino,
aminocarbonyl, or formyl; and pharmaceutically acceptable salts
thereof. The specification also discloses that these compounds
are endothelin receptor antagonists useful in treatment of all
endothelin (ET)-related disorders. A laundry list of diseases to
be treated is disclosed, e.g., hypertension, renal, glomerular,
or mesangial cell disorders, endotoxemia, and ischemia. Dosages
of 0.1-100 mg/Kg/day are disclosed. Three compounds are prepared.
No administration protocol is disclosed nor are there any examples
(in vitro or in vivo) demonstrating the use of any
of the compounds.
Claims:
- A compound of formula
![Chemical Structure 5](images/i5.gif)
or a pharmaceutical acceptable salt thereof, wherein HET is
a 5- or 6-membered heterocyclic ring containing at least one
hetero atom selected from N, S and O, and wherein HET is optionally
substituted with X; and X is hydrogen, lower alkyl, lower alkoxy,
hydroxy, halo, lower monoalkylamino, lower dialkylamino, nitro,
cyano, acylamino, aminocarbonyl, formyl; with the proviso that
HET is not 3,4-dimethyl-5-isoxazolyl.
- A method of treating endothelin-related disorders in a mammal,
which comprises administering to said mammal an effective amount
of a compound of claim 1.
- A method of treating hypertension, which comprises administering
an effective amount of a compound of Claim 1.
- A method of treating renal, glomerular or mesangial cell disorders,
which comprises administering an effective amount of a compound
of Claim 1.
- A method of treating endotoxemia, which comprises administering
an effective amount of a compound of claim 1.
- A method of treating ischemia, which comprises administering
an effective amount of a compound of claim 1.
State of the prior art:
Doherty, Journal of Medicinal Chemistry, Vol. 35, No. 9, 1493-1508
(1992). The Doherty article, last page, clearly evidences that work
in the field of ET receptor antagonism is only in the investigational
stages, the possibility for the need of selectivity towards various
receptor subtypes for treating certain disorders has not been determined
nor has any use for ET-2, ET-3 been elucidated. The article, at page
1504, also teaches that the transition from peptidomimetic structures
to a truly non-peptide lead compound, using "rational design", is
a time-consuming and problematic endeavor.
Clozel et al, Nature, Vol. 365, 759-761 (1993). The Clozel reference
discloses a structurally similar compound, RO 46-2005, (having
an unsubstituted sulfoamide nitrogen) which has been extensively
tested. However, the final paragraph teaches that those tests show
only the potential of ET receptor antagonism as playing
a role in the treatment of vasoconstriction, and that the validity
of ET receptor antagonism in man remains to be determined.
Stein et al, Journal of Medicinal Chemistry, Vol. 37, No. 3, 329-331
(1994). The Stein article, published after the filing date, provides
test data of ETA receptor antagonist, shown in Tables 1 and 2,
of some structurally similar compounds (having an unsubstituted
sulfoamide nitrogen) which are excluded by the instantly claimed
proviso. In Table 2, the IC50 values differ over a 100-fold range
just in changing substituents on the naphthyl ring. This evidences
that small changes in structure will significantly affect the activity.
The article also states, at page 329, right column, "proof that
ET is a causative agent has remained elusive.....".
Analysis:
There is demonstration in the specification that three compounds
have been prepared. It is reasonable to conclude that the specification
does teach how to make the entire scope of the claimed compounds.
The issue is whether the specification teaches one skilled in the
art at the time of filing how to use the invention as claimed.
Based on the undue experimentation factors, particularly the state
of the prior art, the unpredictability, the lack of working examples
and guidance, and the breadth of the claims as evidenced by the
information provided above, the answer would be no. Therefore,
an objection/rejection using form paragraph 7.31.02 would be appropriate.
The Rejection:
Claims 1-6 are rejected under 35 U.S.C. § 112, first paragraph,
because the specification does not enable any person skilled in
the art to which it pertains, or with which it is most nearly connected,
to use the invention.
Claim 1 recites compounds where the only disclosed uses of the
compounds are the methods of treating various endothelin-related
disorders as recited in claims 2-6. The specification discloses
that the compounds act as endothelin receptor antagonists. However,
the Doherty (page 1504), Stein (page 329), and Clozel (last paragraph)
articles clearly establish that the field of effective ET receptor
antagonists and their relation to treating known disease or ischemic
conditions is uncertain. The references clearly evidence that at
the time of filing there is no correlation between any one disorder
and ET much less the laundry list of treatable diseases disclosed
in the specification and claimed in claims 2-6. The references
also provide evidence that the unpredictability in the art is extremely
high. Note that Stein teaches that an unsubstituted sulfoamide
nitrogen was critical to the receptor affinity of this class of
ET receptor antagonists. Yet even for this narrow class of compounds
there is a wide range of receptor binding , see Table 2. Additionally,
receptor binding would be expected to be very much structure sensitive,
see Stein article. Therefore, it is clear that at the time of filing
there was no clear direction or guidance provided by the prior
art to establish that the ET receptor antagonists disclosed (and
claimed) are enabled in use for treatment of disease conditions
such as hypertension, renal disorders, or ischemia.
Furthermore, the instant specification provides no direction or
guidance for how to use the disclosed (and claimed) compounds since
no protocol is set forth, and no working examples are provided.
Although the specification provides a dosage range for treating
conditions related to ET receptor antagonism there is no standard
by which to measure whether the compounds will operate as intended.
There are no guidelines for determination of dosages needed to
provide an anti-hypertensive effect vs. anti-endotoxemia effect
vs. anti-anginal effect, etc. Further, the instant claims embrace
various non art-recognized equivalents of heterocyclics which can
be substituted. The specific compounds made are not seen as adequately
representative of the compounds embraced by the extensive Markush
groups instantly claimed. Therefore, one skilled in the art would
not know how to use the invention as claimed throughout its entire
scope without undue experimentation.
Additional notes:
- If the specification discloses compounds as antagonists for
the ET receptor subtype ETA, which is selective for ET-1 (Doherty),
and provides test data demonstrating that the three compounds
prepared have the activity to inhibit ET-1 binding to vascular
smooth muscle, then the specification would teach how to use
those three compounds as ET-1 receptor antagonists. Claims drawn
to those three compounds should not be rejected.
- If the application is filed Jan. 1995, the specification clearly
discloses compounds are antagonists for the ET receptor subtype
ETA, and provides test data showing greater affinity for ET-1
over ET-3, then at least compounds tested can be used to treat
hypertension. Douglas et al, TiPS, Vol. 15, 313-316 (1994), published
before the filing date, teach that ET antagonists play a direct
role for ET-1 in the maintenance of the elevated blood pressure.
This demonstrates that the state of the prior art at the time
of filing is a very important factor.
Example I: Transgenic Animals
Specification: The specification discloses that -amyloid
precursor protein (-APP) is associated in the art with Alzheimer's
disease. At the time of filing, the art had only been able to diagnose
Alzheimer's disease through the post mortem examination of the
brains of patients who had exhibited the senile behavior characteristic
of Alzheimer's. These examinations revealed the presence of neurofibrillary
tangles formed from large plaques of agglomerated peptides. The
brains show neuronal loss and abnormal morphology of the cells
in the cortex and hippocampus. It was hypothesized in the art that
when -APP is produced, it is cleaved in neuronal cells of the brain
and its degradation product, /A4 protein, forms deposits which
accumulate into plaques and then form tangles which eventually
cause the death of brain cells. However, the specification admits
that the sequelae of events leading to Alzheimer's disease is unknown.
The specification discloses that it would be beneficial to produce
transgenic mice which could be used as a model for Alzheimer's
disease so as to identify agents which can be used as therapeutic
agents for Alzheimer's disease. The specification recognizes that
mice normally produce their own -APP, but do not develop the symptoms
of Alzheimer's disease. Thus, the specification is directed to
the generation of mice which contain in their genome DNA encoding
human /A4 protein. The specification discloses that the transgenic
mice could be used to identify agents which inhibit the formation
of the human /A4 protein. It is hypothesized that such agents would
be useful therapeutics in treating Alzheimer's Disease since without
the formation of the /A4 protein, there would be nothing to cause
the changes associated with Alzheimer's disease.
Specific examples are provided which show the constructs used
to make the mice. These constructs contain a glial-specific promoter
and the coding sequence for /A4 protein. The transgenic mice are
disclosed to express the /A4 protein, as verified by immunohistology.
Some of the transgenic mice additionally exhibit deposits of the
/A4 protein in the brain. None of the mice are disclosed to possess
amyloid plaques or neurofibrillary tangles. There is no disclosure
that the animals were tested for behavioral effects.
Claim:
- A transgenic mouse, all of whose somatic and germ cells contain
a construct which comprises a glial-specific promoter operatively
linked to a DNA sequence which encodes human /A4 protein, said
mouse expressing said construct in its glial cells.
State of the Prior Art:
Selkoe, Nature, Vol. 354, 432-433 (1991).
This reference describes -APP and its relationship to Alzheimer's
disease. The author states that -APP is a normal human protein,
and that deposition of its cleavage product, /A4 protein, is a
normal consequence of aging, and does not signify that a person
will develop Alzheimer's disease. Furthermore, the reference states
that although -APP and /A4 protein are associated with Alzheimer's
disease, no correlation has been found between increased deposition
of these proteins and the disease. In addition, the reference discloses
that the mechanism by which the /A4 protein is formed and proceeds
through the changes that lead to Alzheimer's Disease is unknown,
but since the reference also discloses that the /A4 protein occurs
in normal and Alzheimer's patients, the reference at least suggests
that mechanisms are different in each type of patient.
Analysis:
Since the only disclosed utility for the claimed mouse
is a model for Alzheimer's disease so as to identify agents which
can be used as therapeutic agents for Alzheimer's disease, enablement
for the claimed invention must be based on whether the specification
teaches how to make the claimed mouse and whether the specification
teaches how to use the claimed mouse as a model for Alzheimer's
disease so as to identify agents which can be used as therapeutic
agents for Alzheimer's disease. The working examples in the specification
show that transgenic mice have been generated which express human
/A4 protein in their glial cells. Although some of the mice exhibit
plaque formation, the reference of record indicates that deposition
of /A4 protein does not necessarily indicate Alzheimer's disease
is likely to develop. Furthermore, the reference discloses that
the mechanism by which the /A4 protein is formed and proceeds through
the changes that lead to Alzheimer's Disease is unknown, but since
the reference also discloses that the /A4 protein occurs in normal
and Alzheimer's patients, the reference at least suggests that
mechanisms are different in each type of patient. Thus, it does
not appear that the specification adequately teaches how the mice
could be used as a model for Alzheimer's disease, or what conclusions
could be drawn from the expression and deposition of human /A4
protein observed or the inhibition of human /A4 protein expression
or deposition. Given the state of the art and the lack of guidance
and working examples as to how to use the mice claimed, an enablement
rejection using form paragraph 7.31.02 would be appropriate.
Rejection:
Claim 1 is rejected under 35 U.S.C. 112, first paragraph, because
the specification does not enable any person skilled in the art
to which it pertains, or with which it is most nearly connected,
to use the invention.
The claimed invention is directed to a transgenic mouse which
expresses DNA encoding human /A4 protein in its glial cells. Applicant
discloses that the mouse is useful for the identification of agents
which inhibit human /A4 protein production, leading to therapies
for Alzheimer's disease. However, the art teaches that in Alzheimer's
disease, the patients suffer from neuronal loss and abnormal morphology
of the cells in the hippocampus and cortex. The art does not indicate
that glial cell production of human /A4 protein results in Alzheimer's
Disease or any other disease. Selkoe, which represents the state
of the art at the time the invention was made, does not make a
correlation between an increase in human /A4 protein deposition
and Alzheimer's disease. Indeed, the reference states that deposits
of /A4 protein are found in human and other mammals that never
develop Alzheimer's disease. As far as the disease is understood,
the initial deposit of human /A4 protein must accumulate to form
plaques which in turn lead to neurofibrillary tangles and neuronal
death. Behavioral changes also occur such as inability to learn,
short-term memory loss, etc. Furthermore, Selkoe discloses that
the mechanism by which the /A4 protein is formed and proceeds through
the changes that lead to Alzheimer's Disease is unknown, but since
Selkoe also discloses that the human /A4 protein occurs in normal
and Alzheimer's patients, Selkoe at least suggests that mechanisms
are different in each type of patient. In view of these facts and
the fact that applicant's mice do not exhibit plaque formation
nor any morphological or behavioral indicia specific to Alzheimer's
disease, inhibiting production of the human /A4 protein in the
transgenic mice of the invention specification at best suggests
that the formation of the protein could be inhibited in normal
subjects but does not adequately disclose how to inhibit the formation
of the protein in a patient with Alzheimer's Disease. Thus, given
the unpredictability of the field of the invention, the relative
lack of information available about Alzheimer's disease, and the
lack of correlatability between the observed phenotype of the exemplified
mice and any disease condition, others skilled in the art would
be unable to practice the claimed invention without the exercise
of undue experimentation.
Modifications to the Above Facts: Let us assume that the
specification discloses that the transgenic mice produced actually
exhibited at least one of the symptoms of Alzheimer's disease,
e.g., the presence of neurofibrillary tangles, neuronal loss, and/or
abnormal morphology of the cells like that exhibited in Alzheimer's
disease, and the claim, in addition to the limitations recited
above, recites that the transgenic mouse has the specifically disclosed
phenotype. Does this change the analysis set forth above? The answer
is yes. It would be reasonable to conclude that the disease mechanism
of formation of the /A4 protein is being exhibited in the transgenic
mice. Therefore, inhibiting the formation of the protein would
be reasonably predictive of inhibiting the formation of the protein
in a patient having Alzheimer's disease. Thus, in this case, no
enablement rejection would be made.
In addition, no enablement rejection would be made in a situation
where an enabled use for the claimed transgenic mouse is well established.
Example J: Selectin-Mediated Cellular Adhesion
Specification: The specification discloses a series of
compounds and compositions which are useful as inhibitors of P-selectin-mediated
cellular adhesion. The compounds are disclosed as being effective
in the treatment or prevention of inflammatory diseases such as
rheumatoid arthritis, asthma and allergy conditions, as well as
other pathological conditions including ulcerative colitis and
multiple sclerosis.
The compounds of the invention have the following formula:
![Chemical Structure 6](images/i6.gif)
wherein R1, R2, R3, and R4 each are independently hydrogen, unsubstituted
or substituted alkanoyl, arylalkyl or arylcarbonyl, wherein the
substituent is selected from halogen, C1-4 alkyl, trifluoromethyl,
hydroxy, and C1-4 alkoxy.
The specification provides detailed instruction for the synthesis
of 30 inventive compounds. Furthermore, the specification provides
2 in vitro and 2 in vivo assays demonstrating the
inhibitory effectiveness for 6 of the compounds on P-selectin-mediated
cellular adhesion. The examples also demonstrate that three of
the compounds failed to inhibit P-selectin-mediated cellular adhesion.
General guidelines suggest that the compounds can be formulated
in pharmaceutical compositions by combining them with pharmaceutical
carriers. Several examples of suitable pharmaceutical carriers
are given. The specification further discloses that the pharmaceutical
compositions will contain suitable amounts of one of the compounds
ranging from 0.1 µg/kg to 100mg/kg body weight, depending upon
the type of formulation (systemic, topical, oral) and the particular
disease or condition to be treated. Specific modes of administration
are disclosed.
Claims:
- A compound of the formula:
-
![Chemical Structure 6](images/i6.gif)
wherein R1, R2, R3, and R4 each are independently hydrogen,
unsubstituted or substituted alkanoyl, arylalkyl or arylcarbonyl,
wherein the substituent is selected from halogen, C1-4 alkyl,
trifluoromethyl, hydroxy, and C1-4 alkoxy.
- A pharmaceutical composition for treatment of diseases characterized
by selectin-mediated cellular adhesion comprising a therapeutically
effective amount of a compound of claim 1 with a pharmaceutically
acceptable carrier.
- A method for the treatment of diseases characterized by selectin-mediated
cellular adhesion, comprising administering a therapeutically
effective amount of a compound of claim 1 or a pharmaceutical
composition thereof.
State of the Prior Art:
WO 93/05803. This reference discloses that three human selectin
proteins have thus far been identified, E-selectin (formerly ELAM-1),
L-selectin (formerly LAM-1) and P-selectin (formerly PADGEM or
GMP-140). This reference also discloses that inhibitors of selectin-mediated
cellular adhesion are suitable as anti-inflammatory agents.
Skinner et al., J.Biol. Chem., Vol. 266, 5371-5374 (1991). This
reference discloses that sulfated glycans inhibited the binding
of P-selectin to neutrophils.
Suzuki et al., Biochem. Biophys. Res. Commun., Vol. 190, 426-434,
(1993). This reference discloses that sulfated glycolipids are
inhibitors of cellular adhesion.
Needham et al., Proc. Natl. Acad. Sci. USA, Vol. 90, 1359-1363,
(1993). This reference discloses that sulfoglucuronyl glycosphingolipids
(SGNL lipids) selectively support L- and P-selectin, but not E-selectin
binding.
Mulligan et al., Nature, Vol. 364, 149-151, (1993). This reference
discloses that oligosaccharides have useful protective effects
in P-selectin-dependent lung injuries.
Analysis:
The specification is sufficiently enabling to allow one skilled
in the art to synthesize, without undue experimentation, the glycolipid
compounds comprising the scope of claim 1 and the pharmaceutical
composition comprising the scope of claim 2. Additionally, the
specification does teach how to use 6 of the embodiments encompassed
by claim 1 in the treatment of at least P-selectin-mediated cell
adhesion disorders. Therefore, an enablement rejection using form
paragraph 7.31.02 would not be appropriate. The question is whether
the enabled embodiments are representative of the scope of the
claims. There are two scope issues here. The first is regarding
the scope of the compounds recited and the second is regarding
the scope of selectin-mediated cellular adhesion. The art provides
evidence that all the selectins are involved in mediating cellular
adhesion. Furthermore, references such as Needham et al, Suzuki
et al, and Skinner et al suggest that all the selectins are inhibited
by similar compounds. Thus, the evidence given in the specification
with respect to P-selectin would be expected to be applicable to
at least one of the other selectins also. See Needham et al and
Example 3 of WO 93/05803. It is true that it is not entirely predictable
which compounds will inhibit binding of which selectin. The specification
even provides evidence that some of the compounds meeting the structural
limitations of the claims fail to inhibit P-selectin-mediated cellular
adhesion. However, weighing all the evidence in this case, it would
be reasonable to conclude that while the scope of the claims would
encompass non-operative embodiments, the experimentation needed
to determine the operative embodiments and to use those embodiments
would not be undue. Therefore, it would be reasonable not to make
any enablement or scope rejection in this case.
Example K: HIV
Specification: The specification discloses Protein X, which
is found on the surface of HIV having the amino acid sequence of
SEQ ID NO. 1. The specification teaches the purification of Protein
X from tissue culture supernatants containing HIV-infected cells
and further teaches recombinant DNA methods for producing Protein
X. An expression vector comprising a gene encoding Protein X was
deposited with the ATCC prior to Applicant's filing date. The specification
further discloses a composition containing Protein X and a carrier
suitable for use in immunoassays for diagnosing HIV infection.
The specification further discloses a pharmaceutical composition
comprising Protein X suitable for treating and/or preventing HIV
infection.
The specification also discloses a neutralizing monoclonal antibody
designated Anti-X, specific for Protein X. The hybridoma producing
Anti-X was deposited with the ATCC before Applicant's filing date
as ATCC accession no. HB 12345. The specification discloses a composition
comprising Anti-X suitable for use in decontaminating fluids containing
HIV. The specification further discloses a pharmaceutical composition
comprising Anti-X and a carrier suitable for passive immunization
to treat and/or prevent HIV infection. The specification also discloses
an immunoassay using Anti-X for diagnosing HIV infection.
The specification teaches methods of vaccination for the prevention
of HIV infection by administering a pharmaceutical composition
containing protein X. In support of the claimed invention, the
specification teaches that Protein X injected into mice results
in the production of antibodies which neutralize HIV in vitro as
measured by viral inhibition assays and syncytium inhibition assays.
The specification further teaches a diagnostic assay method comprising
contacting human serum with Protein X and then detecting the presence
of human antibodies bound to Protein X. As evidence, the specification
teaches the use of Protein X in a conventional ELISA assay using
monoclonal antibody tissue culture supernatants. The specification
further discloses that Protein X is useful for producing monoclonal
antibodies suitable for decontaminating fluids containing HIV.
The specification further teaches a method for passive immunization
against HIV by administering a pharmaceutical composition comprising
Anti-X. Finally, the specification teaches a method of decontaminating
a fluid containing HIV by contacting the fluid with Anti-X. The
specification teaches that a concentration of 10 ng of Anti-X/ml
of fluid will neutralize up to 109 HIV particles in both virus
neutralization assays and syncytium inhibition assays thereby decontaminating
the fluid.
The specification provides all the information and assurances
so as to enable the making of all deposited materials. The specification
also discloses specific dosages, administration techniques, and
pharmaceutical carriers for each of the in vivo treatment
methods.
Claims:
- Protein X having the amino acid sequence of SEQ ID NO. 1.
- A composition comprising Protein X and a carrier.
- A pharmaceutical composition suitable for treating HIV infection
comprising the protein of claim 1 and a pharmaceutically acceptable
carrier.
- A vaccine for preventing HIV infection comprising the protein
of claim 1.
- A monoclonal antibody designated Mab X which specifically binds
the protein of claim 1 and which is produced by the hybridoma
having ATCC accession no. HB 12345.
- A composition comprising the antibody of claim 5 and a carrier.
- A pharmaceutical composition suitable for treating HIV infection
comprising the antibody of claim 5 and a pharmaceutically acceptable
carrier.
- A vaccine for preventing HIV infection comprising the antibody
of claim 5.
- A method of treating a subject at risk for HIV infection comprising
administering to the subject a therapeutically effective amount
of the pharmaceutical composition of claims 2 or 7.
- A method of preventing HIV infection in a subject comprising
administering the vaccine of claim 3 in an amount sufficient
to prevent HIV infection.
- A method of passive immunization for preventing HIV infection
comprising administering a therapeutically effective amount of
the pharmaceutical composition of claim 7.
- A method for diagnosing HIV infection in a subject comprising:
- a) contacting a body sample with the protein of claim 1 for
a time sufficient to allow antibodies in the body sample to
bind to the protein;
- b) detecting the binding of said antibodies to said protein,
wherein the binding of said antibodies is diagnostic of HIV
infection.
- A method for diagnosing HIV infection in a subject comprising:
- a) immobilizing Anti-X on a solid support;
- b) contacting said immobilized Anti-X with a body sample
for a time sufficient to allow binding of HIV virions in the
sample to immobilized Anti-X;
- c) detecting the binding of HIV to said immobilized Anti-X,
wherein the binding of HIV is diagnostic of HIV infection.
- An in vitro method for decontaminating a fluid containing
HIV which comprises:
- a) contacting the fluid with the composition of claim 6 under
conditions such that the composition forms a complex with the
HIV;
- b) removing the complex so formed from the fluid, thereby
decontaminating the fluid.
State of the Prior Art:
Well known in the art:
- There are no known vaccines for preventing HIV infection;
- There are no art-accepted animal models for HIV infection;
- Antibodies have been used in HIV diagnostic assays and to remove
substances and contaminants from fluids (affinity chromatography,
autologous bone marrow transplant, etc.).
Specific teachings of the art:
Fahey et al., Clin. exp. Immunol., Vol. 88, 1-5 (1992): No immune-based
therapies for HIV have been shown to be effective; No clear correlations
between various types of therapies and clinical benefits (see page
2, Table 1); Clinical benefits of antibody therapies is entirely
unclear (see page 3, second column, third full paragraph).
Stein et al., CID, Vol. 17, 749-771 (1993): Intravenous immunoglobulins
(IVIG) and passive immunization have not been effective (see pages
750-752). "Many of the approaches...such as the use of immunoglobulins
and adoptive cell transfer, pose significant logistical problems
in terms of expense and sources of donor material, while others
(i.e., treatment with cytokines) are hampered by significant toxicity.
Rational development of many approaches is limited by our current
knowledge of their mechanisms and effects and of the immune system's
complex and overlapping activities" (see page 765, last paragraph).
Fox, Bio/Technology, Vol. 12, (1994): "No therapy has emerged
as a sure winner in the campaign against HIV, not a preventive
vaccine nor any of the immune system-boosting treatments."
Seaver, Genetic Engineering News, pages 10 and 21 (1994): While
monoclonal antibodies in general have found wide use in diagnostic
assays, identification of a particular suitable antibody requires
rigorous testing in the presence of serum proteins (see section
entitled "Diagnostic Success Rates"). Identification of suitable
therapeutic antibodies is even more difficult than finding suitable
diagnostic antibodies (see section entitled "Therapeutic Mabs").
Analysis:
The first question is whether Applicant has enabled one skilled
in the art to make and use the claimed products. As with utility
under 35 U.S.C. § 101, Applicant need only enable a single use
to meet the requirements of 35 U.S.C. § 112, first paragraph. The
major difference is that a single utility will obviate a rejection
under 35 U.S.C. 101 for the entire claim. However, 35 U.S.C. 112,
first paragraph, must have the single use enabled for the whole
claim scope. Applicant has taught how to make Protein X as well
as Anti-X (both with guidance and suitable deposits). Applicant
has further shown that Protein X binds antibodies in assays. Since
such assays for HIV are well known in the art, one skilled in the
art would reasonably conclude that Protein X would function in
a similar manner. Further, Applicant has enabled the use of Anti-X
for decontaminating fluids since it was well known in the art to
use antibodies to remove undesirable contaminants and Applicant's
specification established that Anti-X was suitable for removing
HIV from a fluid. Since Anti-X is enabled, Protein X, necessary
for producing Anti-X, is also useful and, therefore, enabled by
the specification. Thus, claims 1-2, 5-6, 12 and 14 would appear
enabled.
For pharmaceutical compositions and vaccines, the intended use
needs to be considered and given weight. A pharmaceutical composition
has an implied in vivo use and evidence of enablement should
be sufficient to convince one skilled in the art that the pharmaceutical
composition would have some beneficial therapeutic effect. Likewise,
the terminology "vaccine" by definition requires some form of protective immune
response in an individual. With HIV, the art clearly recognizes
that immune-based therapies have not been accepted by those skilled
in the art. Therefore, one must carefully consider the evidence
in the specification in support of in vivo uses. Here, the
specification only teaches an in vivo response in mice to
injections of Protein X. However, the mouse is not an art-accepted
model for HIV. Neither are any in vitro assays accepted
as correlative with in vivo efficacy. Therefore, claims
3-4 and 7-8 would not appear to be enabled by the specification.
Claims 9-11 are directed to various methods for treating or preventing
HIV infection. However, Applicant's only evidence for treatment
and/or prevention is in the mouse. The prior art does not recognize
Applicant's animal model (or any other animal model) as correlating
with efficacy in HIV infections. Nor has Applicant set forth any
other evidence to establish that Protein X or Anti-X can be used
to treat HIV or prevent HIV infections. Thus, the methods of claims
9-11 are not enabled.
Finally, claim 13 is directed to a diagnostic assay for diagnosing
HIV infection using Anti-X. Diagnostic immunoassays using HIV proteins
are well known. While Seaver teaches that monoclonal antibody-based
assays are more difficult to develop than are protein assays, such
as the Protein X assay of claim 12, this does not mean that such
assays can not be developed or have not been developed. Furthermore,
the specification indicates that Protein X is a surface protein
and that the monoclonal antibodies described in the specification
bind it with sufficient strength to actually neutralize the virus.
Because of this strong binding to a surface protein, one of skill
in the art would expect that the claimed method could be used at
least to some extent for the diagnosis of HIV infection. Note,
it is not necessary for an invention to work well to be enabled.
Since neither Seaver nor the rest of the state of the art provide
sufficient reason to doubt the objective enablement of the specification,
claim 13 would appear enabled.
Rejection:
Claims 3-4 and 7-11 are rejected under 35 U.S.C. 112, first paragraph,
because the specification does not enable any person skilled in
the art to which it pertains, or with which it is most nearly connected,
to use the invention.
Applicant's claimed invention is directed to pharmaceutical compositions,
vaccines and methods for diagnosing, treating and preventing HIV
infection. However, the specification does not sufficiently establish
that the pharmaceutical compositions, vaccines and methods can
be used as claimed. The specification only sets forth evidence
in the form of mouse animal model studies and there is insufficient
evidence that such studies correlate with in vivo efficacy
in HIV in humans. It is well known in the art that retroviral infections
in general, and HIV infections in particular, are refractory to
anti-viral therapies, as taught by Fahey et al. The obstacles to
therapy of HIV are well documented in the literature. These obstacles
include: 1) the extensive genomic diversity and mutation rate associated
with the HIV retrovirus, particularly with respect to the gene
encoding the envelope protein; 2) the fact that the modes of viral
transmission include both virus-infected mononuclear cells, which
pass the infecting virus to other cells in a covert manner, as
well as via free virus transmission; 3) the existence of a latent
form of the virus; 4) the ability of the virus to evade immune
responses in the central nervous system due to the blood-brain
barrier; and 5) the complexity and variation of the pathology of
HIV infection in different individuals. The existence of these
obstacles establish that the contemporary knowledge in the art
would not allow one skilled in the art to use the claimed pharmaceutical
compositions and vaccines to treat and/or prevent HIV infection
without undue experimentation.
Further, it is well known in the art that individuals infected
with HIV produce neutralizing antibodies to the virus, yet these
antibodies are not protective and do not prevent the infection
from progressing to its lethal conclusion. Further, as taught by
Fahey et al., clinical trials using a variety of immunologically
based therapies have not yielded successful results in the treatment
and/or prevention of HIV infection. Fahey et al. particularly discloses
that monoclonal antibody therapies have not provided any clinical
benefits and "it is not clear how adding these additional antibodies
would make a difference" (see page 3, second column, third full
paragraph). This is further evidenced by the teachings of Stein
et al. which states that rational development of HIV therapeutics "is
limited by our current knowledge of their mechanisms and effects
and of the immune system's complex and overlapping activities" (see
page 765, last paragraph). The failure of all immune-system-boosting
therapies for treating AIDS is further discussed by Fox (see last
paragraph). Thus, it is clear from the evidence of Fahey et al.,
Stein et al. and Fox, that the ability to treat and/or prevent
HIV infection is highly unpredictable and has met with very little
success. Applicants have not provided any convincing evidence that
their claimed invention is indeed useful as a therapeutic or preventative
for HIV infection and have not provided sufficient guidance to
allow one skilled in the art to practice the claimed invention
without undue experimentation. In the absence of such guidance
and evidence, the specification fails to provide an enabling disclosure.
Example L: Alzheimer's Disease
Specification: The specification discloses compounds of formula
wherein A is a linking group and Ar is phenyl or piperazinyl,
or pharmaceutically acceptable salts thereof. The specification
describes five different linking groups and provides test data
with each compound showing that they specifically bind to muscarinic
receptors. The specification discloses methods for synthesizing
the compounds. The compounds are disclosed for the treatment of
Alzheimer's disease, particularly the cognitive impairment aspect
of the disease, and general dosages, administrations, and pharmaceutical
carriers are described but the specification has no working examples
to demonstrate that the compounds affect the function of the muscarinic
receptor or treat Alzheimer's disease.
Claims:
- A compound of formula
-
wherein A is a linking group and Ar is phenyl or piperazinyl,
or a pharmaceutically acceptable salt thereof.
- A pharmaceutical composition useful for treating Alzheimer's
disease comprising a pharmaceutically acceptable carrier and
a therapeutically-effective amount of a compound as claimed in
claim 1.
- A method of treating Alzheimer's disease in a mammal in need
of such treatment, which comprises administering to said mammal
a therapeutically-effective amount of a compound as claimed in
claim 1.
State of the prior art:
Patel, Journal of Geriatric Psychiatry and Neurology, Vol. 8,
81-95, (1995) - This reference discloses that Alzheimer's disease
is known to be difficult to treat and that there is neither a clear
understanding of the origin and pathophysiology of AD (Alzheimer's
disease) nor an animal model of the illness. See Patel, page 81.
The reference states that the search for an effective cognition-enhancing
therapy for AD has so far proved to be elusive. See Patel, page
90.
Ehlert et al, Life Sciences, Vol. 55, Nos. 25/26, 2135-2145, (1994)
- This reference teaches that 5 different subtypes (M1-M5) of muscarinic
receptors have been discovered, and that the activities and species
variation in distribution are complicated. M2 and M4 are taught
to have selective coupling to inhibition of adenylate cyclase,
while M1-M3-M5 couple to a different hydrolysis, see pages 2137-8.
The reference also provides detailed discussion regarding treatment
of AD with a directly acting muscarinic agonist or an allosteric
muscarinic agonist but specifically states at page 2142 that "no
allosteric agonists for the muscarinic receptor have been described
so far."
Analysis:
There is a description in the specification as to how to synthesize
the claimed compounds. Therefore, the specification clearly teaches
how to make the claimed compounds. Accordingly the question is
whether the specification teaches how to use the claimed compounds.
For claim 1, there is only one explicitly disclosed method for
using the claimed compounds, i.e., the claimed method for treating
Alzheimer's disease. However, since the specification teaches that
the claimed compounds specifically bind to the muscarinic receptor
and Ehlert et al teach that muscarinic receptors can be detected
by their binding characteristics, it would be reasonable to conclude
that the claimed compounds would have a well established use of
detecting the muscarinic receptor and that one of skill in the
art would know how to use the compounds for detecting muscarinic
receptor without undue experimentation. Accordingly, it would be
inappropriate to include claim 1 in a rejection under 35 U.S.C.
112, first paragraph.
With respect to claim 2, the "pharmaceutical", "pharmaceutically
acceptable", and "therapeutically-effective" language in combination
with the fact that the only disclosed pharmaceutical use of the
compositions is for treating Alzheimer's disease leads to the conclusion
that this claim should be evaluated in terms of whether the specification
teaches how to use the compositions for treating Alzheimer's disease.
Since method claim 3 must be evaluated in terms of the recited
use, treating Alzheimer's disease, claims 2-3 should be evaluated
together. In this case, the state of the art teaches the unpredictability
in treating Alzheimer's disease, that there are no acceptable models
for treating Alzheimer's disease, and that there are no know agonists
of the muscarinic receptors known that are sufficient to treat
Alzheimer's disease. Furthermore, while the specification clearly
discloses that the claimed compounds bind to the muscarinic receptors,
there is no indication that the binding effects or activates the
receptor in any way. Binding does not equal activating. This, coupled
with the state of the art teaching that there are no models, leads
to the conclusion that there are no working examples. Therefore,
based on the undue experimentation factors, particularly the unpredictability,
the lack of further guidance, and the lack of working examples
(as evidenced by the information provided by the state of the prior
art), it would be reasonable to conclude that it would require
undue experimentation to use the invention of claims 2-3 and a
rejection using form paragraph 7.31.02 would be appropriate.
Rejection:
Claims 2-3 are rejected under 35 U.S.C. 112, first paragraph,
because the specification does not enable any person skilled in
the art to which it pertains, or with which it is most nearly connected,
to use the invention.
The claims recite compositions for treating Alzheimer's disease
(AD) and methods of using compounds for treating Alzheimer's disease.
AD is arguably the most intractable of all major medical disorders.
Specifically, Patel states at page 81:
To date, there is neither a clear understanding of the origin
and pathophysiology of AD nor an animal model of the illness.
This is also evidence of the extreme difficulty and unpredictability
in treatment of AD. A wide variety of therapeutic strategies for
treating AD is being pursued. The major categories of these strategies
are collected in Table 1 of Patel (page 82). Relevant here is the
Cholinergic Drugs subcategory, and in particular, the subsubcategory "Receptor
Agonists" (see page 84). It can be seen that muscarinic agonists
is just one of many, many strategies being pursued. Patel notes
the unpredictability of using muscarinic agonists to improve cognition
in AD patients.
As Ehlert notes, 5 different subtypes (M1-M5) of muscarinic receptors
have been discovered, and that the activities and species variation
in distribution are complicated. M2 and M4 are taught to have selective
coupling to inhibition of adenylate cyclase, while M1-M3-M5 couple
to a different hydrolysis, see pages 2137-8. Ehlert, page 2142,
suggests that the presence of an allosteric site on the receptor
may actually be the route to an effectiveness not previously shown.
He also observes states:
Although no allosteric agonists for the muscarinic receptor
have been described so far, it is possible that structural modification
of the gallamine molecule could lead to the identification of
a drug that increases the affinity of acetylcholine.
The specification provides data to show that the instant compounds
bind to the muscarinic receptors, but the fact that the compounds
bind to the receptors does not mean that they are muscarinic agonists.
Binding does not equal activation. Accordingly, the specification
fails to provide any working examples. Further, the most recent
research has emphasized the necessity of selectivity. Applicants
have not demonstrated any of this. In addition, there is no teaching
how the data provided permits the determination of an effective
amount for treating AD. Therefore, in view of the unpredictability
in the art, the lack of working examples, and the lack of further
guidance in how to use the claimed compounds and compositions to
actually treat AD, it would require an undue amount of experimentation
to use the claimed inventions.
Example M: Polymers
Specification: The specification discloses methods of making
polymeric articles comprising polyolefins. The specification states
that when the polyolefins are mixed with diphosphites prior to
normal processing into articles, such as by blow molding or extrusion
at temperatures of about 600oC, the presence of the diphosphite
stabilizes the polyolefin containing article against discoloration.
Polyolefins suitable for utilization in the invention are disclosed
as including homopolymers and copolymers of mono-olefins, such
as polyethylene and polypropylene and copolymers of ethylene and
propylene. Crosslinked polyolefins are also disclosed as being
suitable for purposes of the invention. The disclosed crosslinked
polyolefins which are suitable for the invention are those which
have been formulated utilizing conventional peroxide crosslinking
agents for polyolefins, such as dicumyl peroxide and di-t-butyl
peroxide.
The specification discloses that the diphosphites suitable for
use in the invention include bis-(alkylphenyl)pentaerythritol diphosphites
such as bis-(2,4-ditertiarybutylphenyl)pentaerythritol diphosphite.
Several other specific diphosphites are disclosed as are several
different forms for the diphosphites, such as dry powder or dissolved
in a solvent. The specification discloses that when the diphosphites
are employed in the polymeric composition at certain concentrations,
they are effective in stabilizing the polyolefin during thermal
processing conditions against discoloration. The diphosphites are
admixed with the polyolefin prior to processing and at a concentration
of about 0.01 to about 5.0% by weight of the stabilized composition
depending on the particular polyolefin and processing conditions.
The specification explicitly states: "This concentration range
is critical for stabilization against discoloration of the polyolefins
because discoloration readily occurs when the diphosphites are
used at concentrations below or above this concentration range." The
diphosphite stabilizers are preferably employed within a range
of 0.05 to about 2.0%. and most preferably within a range of 0.1
to about 1.0%.
Claims:
- A method of making a polyolefin containing article stabilized
against discoloration comprising forming a composition comprising
a polyolefin and a diphosphite and then processing the composition
to form the article.
- The method of claim 1 wherein the composition includes 0.01
to 5% by weight of the diphosphite.
- The method of claim 2 wherein the composition includes 0.05
to 2% by weight of the diphosphite.
- The method of claim 2 wherein the composition includes 0.1
to 1% by weight of the diphosphite.
State of the Prior Art: It is well known in the art that
diphosphites decompose and, therefore, lose their activity when
exposed to temperatures in excess of 1000oC.
Blow molding and extruding using polyolefins are well known processes
for producing polymeric articles and are carried out at temperatures
ranging from 250oC to 1500oC.
Analysis:
In this case, there are no working examples given in the specification.
However, the lack of any working examples alone cannot serve as
the only reason for making an enablement rejection. The other undue
experimentation factors must also be considered. Here, the art
of making polyolefin containing articles by processes such as blow
molding and extrusion are well known and relatively predictable,
the specification provides ample guidance with respect to polyolefins
and diphosphites suitable for carrying out the invention, and the
claims are limited to producing polyolefin containing articles.
Thus, the other undue experimentation factors appear to point toward
the claimed invention being enabled. The only possible issues regarding
lack of enablement appear to be those dealing with the temperature
of the processing and the concentration of the diphosphite.
Regarding the temperature, the claim is not limited to any particular
processing temperature but it is clear from the state of the art
that the process would not be operative at temperatures above 1000oC
since the diphosphites decompose and become inactive. Since the
specification explicitly discloses processes being carried out
about 600oC, it appears that the claims should be limited to processes
being carried out at about 600oC. However, there is nothing in
the specification which indicates that the temperature of the process
is critical to produce polyolefin containing articles stabilized
against discoloration. Furthermore, the specification need not
disclose what is well known in the art, and preferably omits it,
and the claims can include non-operative embodiments as long as
is does not require undue experimentation to determine which embodiments
are operable. Here, one skilled in the art taking the specification
with the state of the art, would clearly recognize the temperature
limitations of the claimed processes and would be able to determine
which embodiments are operable without undue experimentation. Therefore,
it would be improper to limit the claims to a particular temperature.
Regarding the concentration issue, the specification explicitly
states that when the concentration of the diphosphites in the composition
is outside the range of 0.01 to 5% by weight, the articles are
not stabilized against discoloration and, therefore, the concentration
is critical to the invention. Since claim 1 lacks this critical
limitation, it would be reasonable to reject claim 1 for lack of
enablement using form paragraph 7.33.01. Since claims 2-4 include
concentrations within the critical range, they would not be included
in the rejection. Note, while the specification also states that
narrower concentration ranges are "preferred", this does not mean
that they are critical. Therefore, it would be inappropriate to
limit the claims to these narrower concentrations.
Rejection:
Claim 1 is rejected under 35 U.S.C. 112, first paragraph, as based
on a disclosure which is not enabling. The concentration of the
diphosphite in the composition is critical or essential to the
practice of the invention, but not included in the claim(s) is
not enabled by the disclosure. In re Mayhew, 527 F.2d 1229,
188 USPQ 356 (CCPA 1976). The specification clearly discloses that
the concentration of the diphosphite is critical to the making
of polyolefin containing articles that are stabilized against discoloration
when it states:
This concentration range is critical for stabilization against
discoloration of the polyolefins because discoloration readily
occurs when the diphosphites are used at concentrations below
or above this concentration range.
Therefore, the claim should be limited to such concentrations.
Example N: DNA
Specification: The 50 amino acid peptide, algernin, has
been extracted and isolated from ovine brain. Algernin has been
sequenced and cDNA clones encoding algernin have been isolated
from both sheep and humans. The human cDNA is similar to the ovine
cDNA and encodes the same amino acid sequence as the ovine cDNA.
The specification also discloses probes consisting of 15 or more
consecutive nucleotides from the cDNA sequences encoding ovine
or human algernin and that the probes can be used to isolate the
corresponding cDNA. Specific procedures and working examples are
described for using the probes to isolate the algernin gene as
are specific constructs, procedures and working examples for the
recombinant production of active algernin in prokaryotic and eukaryotic
cells. Preliminary test results with human subjects show that injections
of purified algernin (0.005 mg/kg) increases short term memory
retention by 200% compared to injections of human serum albumin.
Algernin also significantly decreases the time required for mice
to learn to run simple mazes.
TABLE 1 (amino acid sequence of algernin)
Met Phe Arg Val Lys Arg Trp Thr Phe Val Leu Val Val Lys Thr Val
Gln Met
Ala Lys Phe Gln Trp Met Ala Lys Ile Phe Trp Val Trp Thr Val Cys
Val Arg
Thr Val Glu Phe Arg Val Lys Arg Val Val Met Ala Met Lys
TABLE 2 (ovine cDNA for algernin)
ATG TTT CGA GTC AAG AGG TGG ACC TTC GTA TTG GTC GTA AAG ACT GTG
GAG ATG
Met Phe Arg Val Lys Arg Trp Thr Phe Val Leu Val Val Lys Thr Val
Gln Met
GCC AAA TTT GAA TGG ATG GCG AAA ATA TTT TGG GTA TGG ACC GTG TTC
GTA CGG
Ala Lys Phe Gln Trp Met Ala Lys Ile Phe Trp Val Trp Thr Val Cys
Val Arg
ACA GTT GAA TTT CGG GTG AAA CGG GTA GTA ATG GCC ATG AAA TAG
Thr Val Glu Phe Arg Val Lys Arg Val Val Met Ala Met Lys
TABLE 3 (human cDNA for algernin)
ATG TTC CGA GTC AAG AGA TGG ACC TTC GTA TTA GTC GTA AAG ACT GTG
GAG ATG
Met Phe Arg Val Lys Arg Trp Thr Phe Val Leu Val Val Lys Thr Val
Gln Met
GCC AAA TTT GAA TGG ATG GCG AAA ATA TTT TGG GTA TGG ACC GTG TTC
GTA CGG
Ala Lys Phe Gln Trp Met Ala Lys Ile Phe Trp Val Trp Thr Val Cys
Val Arg
ACA GTT GAA TTT CGG GTG AAA CGG GTA GTA ATG GCC ATG AAG TAG
Thr Val Glu Phe Arg Val Lys Arg Val Val Met Ala Met Lys
Claims:
- An isolated cDNA that comprises the following DNA sequence
and encodes algernin:
ATG TTC CGA GTC AAG AGA TGG ACC TTC GTA TTA GTC GTA AAG ACT
GTG GAG ATG GCC AAA TTT GAA TGG ATG GCG AAA ATA TTT TGG GTA
TGG ACC GTG TTC GTA CGG ACA GTT GAA TTT CGG GTG AAA CGG GTA
GTA ATG GCC ATG AAG TAG
or fragments thereof that are at least 15 nucleotides in length.
- An isolated DNA that encodes the following amino acid sequence
for algernin:
Met Phe Arg Val Lys Arg Trp Thr Phe Val Leu Val Val Lys Thr
Val Gln Met Ala Lys Phe Gln Trp Met Ala Lys Ile Phe Trp Val Trp
Thr Val Cys Val Arg Thr Val Glu Phe Arg Val Lys Arg Val Val Met
Ala Met Lys
or fragments thereof that are at least 15 nucleotides in length.
- An isolated DNA that encodes a 50 amino acid peptide that
has algernin activity.
State of the Prior Art:
Ngo et al, The Protein Folding Problem and Tertiary Structure
Prediction, 1994, Merz et al (ed.), Birkhauser, Boston, MA,
pp. 433 and 492-495. This reference teaches that the relationship
between the sequence of a peptide and its tertiary structure
(i.e., its activity) is not well understood and is not predictable.
The state of the prior art is also such that given a specific
sequence it is routine to synthesize DNA and proteins.
Analysis:
Claim 1 is limited to a single DNA sequence and any 15 mer thereof.
Since the state of the art is such that it would have been routine
to make the DNA given the sequence, it certainly would not require
undue experimentation to make the DNAs claimed in claim 1. Furthermore,
the specification clearly shows how to use the full length DNA
to produce algernin and the 15 mers to obtain the full length DNA.
Therefore, it would not require undue experimentation to make or
use the DNAs of claim 1 and no enablement rejection should be made.
For claim 2, the analysis is similar even thought the genus is
very large. There are at least 1.26 x 1021 embodiments of the claim,
but each embodiment can be readily identified using the genetic
code, synthesized using conventional methods, and used in the manner
taught in the specification without undue experimentation.
For claim 3 the analysis is different. Claim 3 is broader than
the enabling disclosure because there is no guidance as to which
(if any) of the 50 amino acids may be changed while algernin activity
is retained. The total number of 50 amino acid peptides is 1.13
X 1065. The number of single amino acid substitutions is 950. The
number of two amino acid substitutions is over 900,000. Since the
relationship between the sequence of a peptide and its tertiary
structure (i.e. its activity) are not well understood and are not
predictable (e.g., see Ngo et al, in The Protein Folding Problem
and Tertiary Structure Prediction, 1994, Merz et al (ed.),
Birkhauser, Boston, MA, pp. 433 and 492-495.), it would require
undue experimentation for one skilled in the art to arrive at other
50 amino acid peptides that have algernin activity. In Amgen
Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed.
Cir. 1991), the court ruled that a claim to a large genus of possible
genetic sequences encoding a protein with a particular function
that needs to be determined subsequent to the construction of the
genetic sequences may not find sufficient support under 35 U.S.C.
112, first paragraph, if only a few of the sequences that meet
the functional limitations of the claim are disclosed and if undue
experimentation would be required of one skilled in the art for
the determination of other genetic sequences that are embraced
by the claim. If it would require undue experimentation to identify
other 50 amino acid peptides that have algernin activity, it certainly
would require undue experimentation to make their corresponding
DNA. Therefore, it would be reasonable to conclude that it would
require undue experimentation to make the entire scope of claim
3. Since there are embodiment within the scope of claim 3 that
are enabled, such as those recited in claims 1 and 2, the rejection
should be made using form paragraph 7.31.03.
Rejection:
Claim 3 is rejected under 35 U.S.C. 112, first paragraph, because
the specification, while being enabling for DNA encoding the amino
acid sequence for algernin, does not reasonably provide enablement
for DNA that encodes other 50 amino acid peptides that have algernin
activity. The specification does not enable any person skilled
in the art to which it pertains, or with which it is most nearly
connected, to make the invention commensurate in scope with these
claims.
Claim 3 recites DNA that encodes any 50 amino acid peptide
as long as the peptide has algernin activity. However, other than
algernin itself, the specification fails to disclose any other
peptide which has algernin activity. Furthermore, the specification
provides no guidance as to which (if any) of the 50 amino acids
may be changed while algernin activity is retained. The total number
of 50 amino acid peptides is 1.13 X 1065. The number of single
amino acid substitutions is 950. The number of two amino acid substitutions
is over 900,000. Because of this lack of guidance, the extended
experimentation that would be required to determine which substitutions
would be acceptable to retain algernin activity, and the fact that
the relationship between the sequence of a peptide and its tertiary
structure (i.e. its activity) are not well understood and are not
predictable (e.g., see Ngo et al, in The Protein Folding Problem
and Tertiary Structure Prediction, 1994, Merz et al (ed.),
Birkhauser, Boston, MA, pp. 433 and 492-495.), it would require
undue experimentation for one skilled in the art to arrive at other
50 amino acid peptides that have algernin activity. In addition,
in Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d
1016 (Fed. Cir. 1991), the court ruled that a claim to a large
genus of possible genetic sequences encoding a protein with a particular
function that needs to be determined subsequent to the construction
of the genetic sequences may not find sufficient support under
35 U.S.C. 112, first paragraph, if only a few of the sequences
that meet the functional limitations of the claim are disclosed
and if undue experimentation would be required of one skilled in
the art for the determination of other genetic sequences that are
embraced by the claim. This is the case here. In other words, since
it would require undue experimentation to identify other 50 amino
acid peptides that have algernin activity, it certainly would require
undue experimentation to make their corresponding DNA and, therefore,
the entire scope of claim 3 is not enabled.
Modifications to the Above Facts: Let us assume that the
specification merely disclosed that the algernin could be used
to increase short term memory retention but does not teach how
to use algernin in this or in any other manner and there is no
well established use for algernin. Also assume that the application
includes a claim directed to a method of making algernin using
cDNA encoding algernin and there is no well established use for
the claimed cDNA. Thus, in this situation, the only disclosed use
for the claimed inventions is making algernin, which the specification
teaches how to do, but the specification fails to teach how to
use algernin. Does this change the analysis set forth above? Put
another way, does the specification need to teach how to use a
product before claims directed to a method of making the product
and claims directed to materials to be used in making the product
are considered enabled? The answer to this last question is yes.
Under these circumstances, a claim drawn to a method of making
the product and claims drawn to materials used in the method of
making the product are not enabled and an appropriate enablement
rejection can be made.
Example O: Vaccines
Specification: The specification relates to Lysobacteria
erythrosis, the microorganism which causes erythrosis, a
slow acting yet deadly disease manifested by the lysis of the
erythrocyte in patients infected with the microorganism. The
disclosure states that l. erythrosis has many proteins
on the surface thereof and that one of these proteins in particular
can induce the immune system to produce antibodies. The specific
surface protein disclosed includes the following peptide which
is responsible for the production of the antibodies:
1 5 10 15
Ser Thr Ile Phe Leu Glu Ser Thr His Glu Asp Ile Ser Glu Ala Ser
Glu
The specification describes compositions including the peptide
and a carrier and teaches that the composition can be used to induce
the immune system, e.g., to produce antibodies which will serve
to vaccinate the host against erythrosis without causing the disease
itself. Specific pharmaceutically acceptable carriers are described
as are specific concentrations of the peptide in the compositions
and suitable modes of administration for generating the immune
response. The specification states that the peptide can be made
using routine peptide synthesis techniques. The specification includes
one example which synthesizes the peptide, places the peptide in
a carrier to form a composition, injects the composition into a
rabbit three times over a period of two months. Three days after
the last injection, the rabbit was bled and antibodies against l.
erythrosis were isolated. The antibodies were contacted with
blood samples from normal patients and those diagnosed with erythrosis.
Binding was present in the samples from the patients with erythrosis
but no binding was present in the samples from normal patients.
It was not demonstrated whether the antibodies were protective
against the disease.
Claims:
- A peptide have the following amino acid sequence:
Ser Thr Ile Phe Leu Glu Ser Thr His Glu Asp Ile Ser Glu Ala
Ser Glu.
- 2. A vaccine comprising the peptide of claim 1 and a pharmaceutically
acceptable carrier.
- 3. A method of inducing an immune response in a host comprising
administering to the host a composition comprising the peptide
of claim 1 and a carrier.
State of the Prior Art: Diagnostic assays for erythrosis
are known in the art. Those assays typically utilize antibodies
against surface antigens of l. erythrosis, contact the antibodies
with blood samples from a patient, and check for any antibody binding,
wherein any binding is indicative of the presence of the microorganism.
Nathaniel et al (this is a fictitious reference) - This reference
teaches that no vaccines for erythrosis are known. While there
have been many attempts at producing a vaccine, all have resulted
in failure. Erythrosis is known only to affect humans. While the
microorganism will infect other mammals, no other mammal other
than humans get the disease. No animal models are recognized as
being predictive of vaccination in humans.
Analysis:
For claim 1, the specification discloses how to make the claimed
peptide. Furthermore, while the only explicitly disclosed use for
the peptide is as a vaccine, which may not be enabled, the example
taken with the state of the prior art implies a well established
utility of using the peptide to raise antibodies for using in assays
for erythrosis. Since one would know how to use the peptides and
the resultant antibodies from the specification and the state of
the art without undue experimentation, it would be inappropriate
to reject claim 1 for lack of enablement.
With respect to claim 2, the "vaccine" and "pharmaceutically acceptable
carrier" language in combination with the fact that the only disclosed
pharmaceutical use of the compositions is for a vaccine leads to
the conclusion that this claim should be evaluated in terms of
whether the specification teaches how to make and use the composition
as a vaccine. While the specification provides some guidance regarding
vaccination, it would be reasonable to conclude that it would require
an undue amount of experimentation to use the composition as a
vaccine in view of the unpredictability in the art and the lack
of working examples. For the reasons set forth above with respect
to claim 1, it is clear that non-vaccine compositions would be
enabled. Since some compositions are enabled, it would be best
to make a scope rejection using form paragraph 7.31.03.
Claim 3 is a broad claim. When read in light of the specification
and the state of the prior art, it covers methods of producing
antibodies for use in diagnostic assays as well as vaccination.
Thus, claim 3 must be evaluated as to whether the specification
enables the entire scope of the claim. From the above discussion
with respect to claims 1 and 2, it is clear that the specification
enables the method to the degree that it encompasses producing
antibodies, but not to the degree that it encompasses vaccination.
Therefore, it would be reasonable to make a scope rejection using
form paragraph 7.31.03.
Rejection:
Claims 2-3 are rejected under 35 U.S.C. 112, first paragraph,
because the specification, while enabled for non-vaccine compositions
and non-vaccination methods of inducing an immune response, does
not reasonably provide enablement for vaccine compositions and
their use in vaccination against erythrosis. The specification
does not enable any person skilled in the art to which it pertains,
or with which it is most nearly connected, to make and use the
invention commensurate in scope with these claims.
Claims 2 is directed to a vaccine, the only disclosed use being
vaccination against erythrosis. Claim 3 is directed to a method
which encompasses the use of the peptide for vaccination against
erythrosis. However, the specification fails to adequately teach
how to use the composition and method for vaccinating against erythrosis.
Erythrosis is a deadly disease and many attempts at producing a
vaccine have been made with no success. This is evidenced by Nathaniel
et al. Thus, the art of vaccinating against erythrosis is not predictable.
While the specification does provide some general guidance with
respect to how to use the vaccine, there are no working examples
since the induction of antibodies in rabbits does not necessarily
mean that the antibodies are protective, since humans are the only
ones afflicted with the disease, and since the rabbits do not constitute
a recognized animal model as is apparent from the state of the
prior art. In view of the absence of working examples for vaccinating
against erythrosis, the breadth of the claims, and the unpredictable
state of the art with respect to vaccinating against erythrosis,
it would require undue experimentation for one skilled in the art
to practice the entire scope of the claimed invention.
If claims 2 and 3 were limited as follows, this rejection would
be overcome:
- 2. A composition comprising the peptide of claim 1 and a carrier.
- 3. A method of producing antibodies which recognize lysobacteria
erythrosis in a host comprising administering to the host
a composition comprising the peptide of claim 1 and a carrier.
REFERENCE LIST
EXAMPLE A:
Wallace et al, Methods Enzymol. 152:432-443 (1987).
Sambrook et al, Molecular Cloning, A Laboratory Manual,
Second Edition, 1989, Cold Spring Harbor Laboratory, Cold Spring
Harbor, NY, p. 11.47.
EXAMPLE B:
Wallace et al, Methods Enzymol. 152:432-443 (1987).
Sambrook et al, Molecular Cloning, A Laboratory Manual,
Second Edition, 1989, Cold Spring Harbor Laboratory, Cold Spring
Harbor, NY, p. 11.47.
EXAMPLE C:
NONE
EXAMPLE D:
NONE
EXAMPLE E:
Zhang et al, Nature, Vol. 372, pp. 425-432, December 1994.
Rink, Nature, Vol. 372, pp. 406-407, December 1994.
Marx, Science, Vol. 266, pp. 1477-1478, December 1994.
EXAMPLE F:
U.S. Patent No. 4,605,661
U.S. Patent No. 4,916,144
Internal Medicine, 4th Edition, Editor-in-Chief Jay Stein, Chapters
71-72, pages 699-715.
EXAMPLE G:
Orkin et al., December 7, 1995, "Report and Recommendation of
the Panel to Assess the NIH Investmen in Research on Gene Therapy",
issued by the National Institutes of Health.
EXAMPLE H:
Doherty, Journal of Medicinal Chemistry, Vol. 35, No. 9, 1493-1508
(1992).
Clozel et al, Nature, Vol. 365, 759-761 (1993).
Stein et al, Journal of Medicinal Chemistry, Vol. 37, No. 3, 329-331
(1994).
EXAMPLE I:
Selkoe, Nature, Vol. 354, 432-433 (1991).
EXAMPLE J:
WO 93/05803.
Skinner et al., J.Biol. Chem., Vol. 266, 5371-5374 (1991).
Suzuki et al., Biochem. Biophys. Res. Commun., Vol. 190, 426-434,
(1993).
Needham et al., Proc. Natl. Acad. Sci. USA, Vol. 90, 1359-1363,
(1993).
Mulligan et al., Nature, Vol. 364, 149-151, (1993).
EXAMPLE K:
Fahey et al., Clin. exp. Immunol., Vol. 88, 1-5 (1992).
Stein et al., CID, Vol. 17, 749-771 (1993).
Fox, Bio/Technology, Vol. 12, 128 (1994).
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EXAMPLE L:
Patel, Journal of Geriatric Psychiatry and Neurology, Vol. 8,
81-95, (1995).
Ehlert et al, Life Sciences, Vol. 55, Nos. 25/26, 2135-2145, (1994).
EXAMPLE M:
NONE
EXAMPLE N:
Ngo et al, The Protein Folding Problem and Tertiary Structure
Prediction, 1994, Merz et al (ed.), Birkhauser, Boston, MA,
pp. 433 and 492-495.
EXAMPLE O:
NONE |
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