DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
2. Applicant's election with traverse of Group I, claims 1-4 and 7, and the following species elections:
Antibody B6 with CDR1-3 as SEQ ID NOs: 9-11, respectively;
There appears to be a typo in which Applicant stated that antibody B6 binds to CTLDV CP. Examiner is interpreting this as CLRDV CP as written in the claims;
in the reply filed on 28 July 2026 is acknowledged. The traversal is on the grounds that Groups II and II depend from the claims of Group I and thus are not distinct. In addition, Applicant argues that according to 37 CFR 1.141(b), a three way requirement for restriction between a product, process of making, and process of use can only be made when the process of making is distinct from the product. This is not found persuasive because neither Group II nor III are drawn to methods of making the antibody of claim 1. As discussed in the Requirement for Restriction/Election mailed 17 June 2026, Group I is both independent and distinct from Groups II and III due to their respective distinctness tests, as well as their different classifications and statuses in the art. Thus, the requirement is still deemed proper and is therefore made FINAL.
Claims 5-6 and 8-16 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 28 July 2026.
Claim Status
3. Claims 5-6 and 8-16 are withdrawn.
Claims 1-4 and 7 are under consideration.
Information Disclosure Statement
4. The information disclosure statement (IDS) submitted on 08 February 2024 was filed before the mailing date of the Non-Final Office Action. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
5. The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Nucleotide and/or Amino Acid Sequence Disclosures
6. Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
7. Specific deficiency - Sequences appearing in the specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
See ¶ [0044] and [0045] of the Instant Specification.
Specification
8. Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
Claim Interpretation
9. The Instant Specification defines “antibody” as “an immunoglobulin molecule” (¶ [0039]) and “single-chain antibody” as “a camelid monomeric antigen-specific VHH domain” (¶ [0040]). Therefore, Examiner is interpreting the “single-chain antibody” of the Instant claims to be a VHH molecule. The broadest reasonable interpretation of the “antigen-binding fragment thereof” could be a single CDR.
Claim Rejections - 35 USC § 112(b)
10. The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
11. Claims 3-4 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 3-4, “a sequence” recited before each SEQ ID NO can be interpreted as requiring the full sequence of the sequence recited or a partial sequence thereof. Therefore, these claims can have multiple structural interpretations. See Ex parte Miyazaki, 89 USPQ2d 1207 (BPAI 2008) ("[R]ather than requiring that the claims are insolubly ambiguous, we hold that if a claim is amenable to two or more plausible claim constructions, the USPTO is justified in requiring the applicant to more precisely define the metes and bounds of the claimed invention by holding the claim unpatentable under 35 U.S.C. §112, second paragraph, as indefinite.").
Claim 4, which is dependent on claim 3, is similarly rejected.
Claim Rejections – Improper Markush Grouping
12. Claims 2-4 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of claims 2-4 is improper because the alternatives defined by the Markush grouping do not share both a substantial structural similarity and a common use for the following reasons: the targets of the two antibodies of claim 2 differ and so the common use of the two species differs. In addition, the different function would require different CDR sets between the two options and since it is the CDR set that determines antibody function, it is the substantial structural feature antibody species of a proper grouping must share. For the reasons above, those embodied by the group of claim 2 are not species that make a proper Markush group. Similarly, the CDRs defining the single-chain antibodies of claims 3-4 have differences and thus there is no CDR set shared among all species to yield a presumed common function. Thus, the Markush grouping of these claims is not proper and they are rejected here as well.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 112(d)
13. The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
14. Claim 7 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. A single-chain antibody or antigen-binding fragment thereof is a composition of matter as is. Therefore, claim 7 does not further limit claim 1 on which it depends. Applicant may cancel the claim, amend the claim to place the claim in proper dependent form, rewrite the claim in independent form so long as no duplicates are made, or present a sufficient showing that the dependent claim complies with the statutory requirements.
Claim Rejections - 35 USC § 112(a) – Written Description
15. The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—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 or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
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.
16. Claims 2-4 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims above are drawn to a single-chain antibody or antigen-binding fragment thereof. The “fragment” reads on truncated peptides and “a sequence as set forth in” could allow for truncated or mutated CDRs. Thus, in the claims rejected above, no antibody molecule is defined by a complete set of parental CDRs in all embodiments. However, the specification only shows working examples with the B6 antibody with a full set of 3 CDRs (SEQ ID NOs: 9-11) and does not contemplate any specific fragments or mutations. Thus, it is clear that the breadth of the recited peptides in the claims far overreaches Applicant’s contribution as disclosed in the specification and so this rejection is made. One of ordinary skill in this art cannot conclude that Applicant was in possession of just any mutation of the B6 antibody. An enormous breadth of potential B6 antibody fragments are thus not represented by Applicant at all. Even if the prior art is aware of additional B6 antibodies, the totality of known mutated B6 antibodies would not be representative of the entire genus for the reasons discussed below.
On 22 February 2018, the USPTO provided a Memorandum clarifying the Written Description Guidelines for claims drawn to antibodies. That Memorandum indicates that, in compliance with recent legal decisions, the disclosure of a fully characterized antigen no longer is sufficient written description of an antibody to that antigen. Accordingly, the instant claims have been evaluated in view of that guidance.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
An applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613.
Furthermore, to satisfy the written description requirement for the genus antibody with specific epitope, Applicant must adequately describe representative antibodies to reflect the structural diversity of the claimed genus. See Eli Lilly, 119 F.3d at 1568 (“[N]aming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”); Fiers v. Revel, 984 F.2d 1164, 1171 (Fed. Cir. 1993) (“Claiming all DNA[s] that achieve a result without defining what means will do so is not in compliance with the description requirement; it is an attempt to preempt the future before it has arrived.”).
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 759 F.3d 1285, 111 USPQ2d 1780 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, as here in which the peptide inhibitors can have any sequence, one must describe a sufficient variety of species to reflect the variation within the genus. However, one of skill in this art cannot envision the structure of any other peptides with the required function other than the few species provided by Applicant and the prior art. Therefore, since only a few species are provided to represent the genus, the claims encompassing the same clearly fail the written description requirement.
Functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. See ABBVIE DEUTSCHLAND GMBH & 2 CO. v. JANSSEN BIOTECH, INC., Appeals from the United States District Court for the District of Massachusetts in Nos. 09-CV-11340-FDS, 10-CV-40003-FDS, and 10-CV-40004-FDS, Judge F. Dennis Saylor, IV. See also Ariad, 598 F.3d at 1351 (“[T]he level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology.”); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1352 (Fed. Cir. 2011) (noting the technical challenges in developing fully human antibodies of a known human protein).
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The recitation of a functional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of the genus must be capable of doing, not of the substance and structure of the members. The Federal Circuit has cautioned that, for claims reciting a genus of antibodies with particular functional properties (e.g., high affinity, neutralization activity, competing with a reference antibody for binding), “[c]laiming antibodies with specific properties, e.g., an antibody that binds to human TNF-α with A2 specificity, can result in a claim that does not meet written description even if the human TNF-α protein is disclosed because antibodies with those properties have not been adequately described."
Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875, 1877-78 (Fed. Cir. 2011).
“Functional” terminology may be used “when the art has established a correlation between structure and function” but “merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing one has invented a genus and not just a species.” Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010). Applicant only teaches one B6 antibody. Since the CDR set of each antibody is responsible for antigen binding function of an antibody, and said set varies structurally from antibody to antibody, there is no correlation between structure and function between the members of an antibody genus. One cannot “represent” the entire genus defined only by function with any structural consensus. Thus, functional language should not be used to define an antibody genus. Rather, structure should be used.
Even when several species are disclosed, these are not necessarily representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus.”). Thus, when there is substantial variation within the genus, as here, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. Since the genus recited in the instant claims is large, it would be very challenging to describe sufficient species to cover the structures of the entire genus.
Overall, at the time the invention was made, the level of skill for preparing antibodies and then selecting those antibodies with desired functional properties was high. However, even if a selection procedure was, at the time of the invention, sufficient to enable the skilled artisan to identify antibodies with the recited functional properties, the written description provision of 35 U.S.C § 112 is severable from its enablement provision. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336 (Fed. Cir. 2010); see also Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1876 (Fed. Cir. 2011) (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.”) Absent the conserved structure provided by all three CDRs of a single-chain antibody in the context of an appropriate VHH framework sequence, the skilled artisan generally would not be able to visualize or otherwise predict, a priori, what an antibody with a particular set of functional properties would look like structurally. Since no mutations are taught in the specification of the recited genus above, the instant claims above clearly fail the written description requirement. A representative number of species has not been taught to describe such a massive genus. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe said genus.
Since only a single species of antibody are taught within the claimed genera above, those that bind the recited epitopes, the instant claims above clearly fail the written description requirement. A representative number of species has not been taught to describe these genera. Given the well-known high level of polymorphism of immunoglobulins / antibodies, the skilled artisan would not have been in possession of the vast repertoire of antibodies and the unlimited number of antibodies encompassed by the claimed invention; one of skill in the art would conclude that applicant was not in possession of the structural attributes of a representative number of species possessed by the members of the genera of every single-chain antibody that binds CLRDV CP or NRTD, broadly encompassed by the claimed invention. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genera.
Owed to the variation among antibodies with respect to their CDRs, the structure of antibodies that correlates with their function, it is very difficult to provide adequate representation of a functionally defined antibody genus. There is unlikely to be any CDR structure shared by the entire genus, for example. Also, the disclosure of one set of antibody CDRs does not guide one of skill to the next set of CDRs. This is because it is well-known in this art that mutation of CDR residues leads to loss of antigen binding. Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff (1982, PNAS, 79: 1979-1983). Rudikoff teaches that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function (Abstract). Thus, while applicant has described one or a few species within each of the genera recited, and the art may provide more, each genus is very large and would encompass antibody structures (CDR sets) that cannot be visualized from the prior art or instant disclosure. One of skill in this art cannot determine the antibody structures encompassed by the claimed genera only defined by function. Any future antibody structure may or may not be encompassed, and if it is, it would not have been represented in Applicant’s disclosed species. Thus, the described species cannot be considered representative of the recited genera of antibodies. E.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, the claims are rejected here.
The art teaches that protein chemistry is probably one of the most unpredictable areas of biotechnology. For example, replacement of a single “lysine” residue at position 118 of acidic fibroblast growth factor by “glutamic acid” led to the substantial loss of heparin binding, receptor binding and biological activity of the protein (Burgess, 1990, J. Cell Bio., 111: 2129-2138). In transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen (Lazar, 1988, Molecular and Cellular Biology, 8: 1247-1252). As these references illustrate, it is unpredictable that a polypeptide variant of a known target protein binder will also bind said target. It is also unpredictable that they would bind said target in the same way, having the same effect on the target (i.e. inhibit or activate). Ju (1991, PNAS, 88: 2658-2662) teaches that the interleukin 1 receptor (IL-1R) antagonist IL-1ra is a naturally occurring protein with no agonist activity in vitro or in vivo (Abstract). However, substitution of a single amino acid lysine145 to aspartic acid changes the property of this peptide to a partial agonist of IL-1R (Abstract). Thus, even a single substitution can change the biological property of a peptide.
This substitution need not be at a position where said residue would contact the target protein. Baker (2000, Immunity, 13: 475-484) teaches that Tax-peptide is an agonist of the of T cell activity (Abstract). However, mutation of proline at position 6 of this peptide to alanine creates a T cell antagonist (Abstract). Importantly, this residue does not contact the T cell receptor (Abstract).
In summary, these examples teach that the biological function of peptide variants is unpredictable because even a single mutation can abolish activity or give a different function. For example, agonist and antagonist peptides can be interconverted through mutagenesis. Importantly, binding can still occur after mutation, illustrating that a simple show of binding is not predictive of the nature of a peptide’s biological activity. This point is underlined by Montrose-Rafizadeh (1997, J. Biol. Chem., 272: 21201-21206) who teaches that receptor binding does not predict agonist or antagonist activity (Page 21205, Column 2, ¶ first full).
Thus, while applicant has described a few species within the genus recited, and the art may provide more, each genus is very large and would encompass peptide structures that cannot be visualized from the prior art or instant disclosure. One of skill in this art cannot determine the peptide structures encompassed by the claimed/recited genus only defined by function. Any future peptide may or may not be encompassed, and if it is, it would not have been represented in Applicant’s disclosed species. Thus, the described species cannot be considered representative of the entire recited genus of peptides. E.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, the claims are rejected here.
As discussed above, an applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613. Therefore, it is recommended that the instant claims be amended to recite all parental CDRs of the species disclosed since it is these structures together that are required to bind the recited antigen.
Claim Rejections - 35 USC § 112(a) – Enablement
17. In making a determination as to whether an application has met the requirements forenablement under 35 U.S.C. 112 ¶ 1, the courts have put forth a series of factors. See, In reWands, 8 USPQ2d 1400, at 1404 (CAFC 1988). The factors considered include: (1) the breadth of the claims, (2) the nature of the invention, (3) the relative skill of those in the art, (4) the presence or absence of working examples, (5) the amount of direction or guidance provided, (6) the state of the prior art, (7) the level of predictability in the art, and (8) the quantity of experimentation necessary.
18. Claims 1-4 and 7 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a single-chain antibody comprising a full set of parental CDRs, does not reasonably provide enablement for any antibody molecule with fewer than all parental CDRs or mutated/truncated CDRs. 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.
The claims are drawn to a single-chain antibody or antigen-binding fragment thereof that binds to CLRDV.
The nature of the invention is an anti-CLRDV single-chain antibody and composition thereof.
The level of skill of one of ordinary skill in this art is high.
The specification provides working examples for producing and sequencing a single-chain antibody with a full set of parental CDRs from alpacas, but does not provide working examples for any antibody molecule with fewer than all parental CDRs or mutated/truncated CDRs. In addition, most antibodies within the full breadth of the claims are highly unpredictable in function and would require an undue amount of experimentation in order to reproduce and use as discussed infra.
The instant claims read on a single-chain antibody that have the CDR sequences claimed. Antibodies defined by fewer than all parental CDRs, in this case three, are not enabled. The minimal enabled single-chain antibody structure of a claim includes three complete parental CDRs.
Nanobodies/VHHs as in the instant claims also require proper framework but instead of six CDRs, can bind antigen with only three CDRs. Yau (2005, Journal of Immunological Methods, 297: 213-224) teaches this (Page 214, Column 1, ¶ 1). All three are important for antigen binding as demonstrated by the randomization of all three CDRs in the work of Yau (Figure 1). Importantly, the work of Yau also demonstrates the unpredictability of nanobody CDR mutation and the ability of identifying functional nanobody with only one CDR defined. Table 1 shows that CDR mutation leads to unpredictable results, unknown until binding is actually tested. Mutation of CDRs led to loss of substantial antigen binding in several cases, as in Gp3. In addition, one can compare D7 with D8 and see that even when fewer than all three parental CDRs are kept constant, the results are unpredictable. D8 and D7 share a CDR3 but have very different affinities. Tiller (04 September 2017, Frontiers in Immunology, 8(986)) also demonstrates that CDR mutation in VHH antibodies is unpredictable (Figure 2A and 2B). Furthermore, it is not possible to test every single mutation/variant of CDRs because the library required would be too large (Page 2, ¶ 2). In summary, all three parental CDRs in a camelid antibody/VHH/nanobody participate and are important for antigen binding. Their mutation leads to unpredictable results. Defining such a nanobody by a single parental CDR also leads to unpredictable results, including loss of antigen binding, since the two other CDRs must be identified by screening with no expectation of success, owed to the unpredictability of this art. This loss of antigen binding via parental CDR mutation is also known for conventional antibodies. Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff (1982, PNAS, 79: 1979-1983). Rudikoff teaches that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function.
Not knowing, absent further experimentation, which modifications function and which do not, when, as set forth above, even a single change of an encoded amino acid can unpredictably affect structure and function, leads to one having no predictability or expectation of success for the function of any given antibody/nanobody modification. Such random experimentation to identify at a later time what structure or fragment or modification is or is not functional and is embraced by applicant’s claims is undue experimentation. Note that an enabling disclosure for the preparation and use of only a few analogs of a product does not enable all possible analogs where the characteristics of the analogs are unpredictable. See Amgen Inc. v. Chugai Pharmaceutical Co. Ltd. (18 USPQ 2d 1027 (CAFC 1991)).
Thus, the state of the art recognized that it would be highly unpredictable that a specific nanobody comprising less than all three parental CDRs known to bind antigen would have antigen binding function. The minimal structure which the skilled artisan would consider predictive of the function of binding the antigen of a nanobody includes three parental CDRs in the context of framework sequences which maintain their correct spatial orientation and have the requisite binding function. One of skill in the art would neither expect nor predict the appropriate functioning of the nanobodies recited in the claimed methods as broadly as currently claimed.
Moreover, claims not containing elements critical or essential to the practice of the invention (in this case three parental CDRs), such as antibodies or antibody fragments not having all of the relevant functional complementarity determining regions (CDRs) in the proper site on an appropriate antibody heavy or light chain framework, are not enabled by the disclosure. See In re Mayhew, 527 F.2d 1229, 188 USPQ 356 (CCPA 1976).
Claim Rejections - 35 USC § 103
19. The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
20. The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
21. Claims 1-2 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Hoffmann (13 July 2022, Front. Plant. Sci., 13: 814119) in view of Vincke (01 January 2012, Antibody Engineering, Chapter 8, 145-176), Kulkarni (19 March 2021, Molecular Immunology, 134: 102-108), and Woodham (01 July 2018, Cancer Immunology Research, 6(7): 870-880).
Regarding claims 1-2 and 7, Hoffmann teaches using peptides on the CLRDV coat protein to produce monoclonal and polyclonal antibodies (Abstract). For the generation of polyclonal antibodies the peptides in Table 1 were used. For the generation of monoclonal antibodies, the GQE and PRN peptides of Table 1 were used, in addition to the α-NKF 14 amino acid peptide, NKFGITKNGRKQFA. (Materials and Methods, ¶ 2). Hoffmann does not teach making a single-chain antibody.
However, Vincke teaches “a step-by-step description to immunize a camelid, to clone the VHH repertoire from the immunized animal, to enrich and select the antigen-specific Nanobodies within this library.” (Page 146, ¶ 3; See also section 3. Methods). Therefore, it would have been obvious to one of ordinary skill at the time of filing to take the methods of Vincke and immunize a camelid with the peptides of Hoffmann to produce a single-chain antibody. The combination of familiar elements is likely to be obvious when it does no more than yield predictable results. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, A.). A rationale to support a conclusion that a claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395 (2007) (see MPEP §§ 2143, A. and 2143.02).
It would be further obvious to make a single-chain antibody against the CLRDV coat protein, as the Board of Patent Appeals and Interferences has taken the position that once an antigen has been isolated, the manufacture of monoclonal antibodies against it is prima facie obvious. See Ex parte Ehrlich, 3 USPQ 2d 1011 (PTO BPAI, 1987) and Ex parte Sugimoto, 14 USPQ 2d 1312 (PTO BPAI, 1990). Camelid antibodies are a type of monoclonal antibody and so this further supports the finding of obviousness. In addition, VHH are smaller than murine antibodies and a person of ordinary skill understands that this gives them increased tissue penetrance. This is supported by Kulkarni, “VHH domains are increasingly being utilized as “next generation” antibodies, as they have unique biochemical and structural properties including high pH stability as well as a lower molecular weight allowing for increased tissue penetration” (Abstract). For the advantage of generating a diagnostic or pharmaceutical antibody against CLRDV with enhanced penetrance, it would have been obvious to produce the obvious VHH supra. A rationale to support a conclusion that a claim would have been obvious is that there is some teaching, suggestion, or motivation in the prior art or in the knowledge generally available to one of ordinary skill in the art to modify the reference or combine reference teachings, and the modification or combination would have a reasonable expectation of success. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395 (2007) (see MPEP §§ 2143, G. and 2143.02).
Additionally, Woodham teaches conjugating an VHH antibody to an antigen, such as an E7 epitope for HPV vaccination, and adding an adjuvant to make a vaccine (In Vivo experiments, ¶ 1). Therefore, it would have been obvious to one of ordinary skill to take the CLRDV single-chain antibody made obvious supra and further incorporate it into a therapeutic composition, as suggested by Woodham. The combination of familiar elements is likely to be obvious when it does no more than yield predictable results. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, A.). A rationale to support a conclusion that a claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395 (2007) (see MPEP §§ 2143, A. and 2143.02).
Art-Free Subject Matter
22. A single-chain antibody with SEQ ID NOs: 9-11 as CDR1-3, respectively, is currently free of the prior art.
Conclusion
23. No claim is allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to KRISTINA E LY whose telephone number is (571)272-5169. The examiner can normally be reached Monday - Thursday, 8:00 am - 5:00 pm EST.
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/KRISTINA E. LY/Examiner, Art Unit 1671 /Michael Allen/Supervisory Patent Examiner, Art Unit 1671
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