Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
Claims 1, 4, 5, 9, 11-13 have been amended in the 5/27/26 reply. Claims 2, 3, and 6-8 are canceled. Claims 15-19 are new. Claims 1, 4, 5, and 9-19 are pending and under examination.
Claim Objections
The objection to claim 13 is withdrawn in light of the claim amendment.
Specification
The objection to the specification is withdrawn in light of the substitute specification and replacement sequence listing filed with the 5/27/26 reply.
Drawings
The objection to the drawings is withdrawn in light of the replacement sheets submitted with the 5/27/26 reply.
Double Patenting
The rejection for nonstatutory double patenting is overcome in light of the claim amendments.
Claim Rejections - 35 USC § 112
The rejection under 35 U.S.C. 112(b) is withdrawn in light of the claim amendments and cancellations.
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.
Claims 1, 4, 5, and 9-19 are/remain 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.
Claim 1 has been amended to require that the antibody or antigen-binding fragment thereof specifically binds to a conformational epitope of protein A56, wherein the conformational epitope of protein A56 “consists of amino acid residues at positions 46 to 101” of SEQ ID NO: 1. It is unclear whether the antibody/fragment binds to every amino acid within the region of amino acids 46-101 or whether it may bind only a subset. The question of claim breadth is further complicated by the requirement that some nucleophilic amino acid of the antibody forms a hydrogen bond with K61 or K91 of SEQ ID NO: 1. The “or” tends to support an interpretation in which the antibody/fragment binds only a subset within the 46-101 region, but the claim also requires that the conformational epitope “consists of” residues within that region. The two interpretations are confusing, so the scope of the claim is unclear.
In addition, claim 1 at line 6 requires that “a nucleophilic amino acid of the antibody forms a hydrogen bond.” Line 6 omits the option for the claimed molecule to be an antigen-binding fragment of the antibody. It is unclear whether the hydrogen-bond limitation applies only to those embodiments in which the molecule is an entire, intact antibody.
Claims 4, 5, and 9-19 depend from claim 1 and do not rectify the indefiniteness, so they must also be rejected under 35 U.S.C. 112(b).
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.
Claims 1, 4, 5, and 9-19 are/remain 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 contain 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 inventors, at the time the application was filed, had possession of the claimed invention.
Claim 1, from which all claims depend, is broadly interpreted as being drawn to a antibody or antigen-binding fragment thereof that specifically binds to a conformational epitope of A56 protein consisting of some unspecified number of amino acid residues at positions 46 through 101 of the amino acid sequence of SEQ ID NO: 1 (protein A56). Critically, claim 1 is open to all antibodies and antigen-binding fragments that bind to any of the residues within the 56-amino-acid conformational-epitope portion of A56. Claim 1 newly requires that the claimed antibody or antigen-binding fragment competes for binding to A56 with one of ten antibodies, each identified by six CDR sequences, and it also newly requires that the claimed antibody or antigen-binding fragment binds to A56 with a particular KD as measured by surface plasmon resonance. The as-filed disclosure does not demonstrate possession of the breadth of the claims in view of the prior and contemporaneous art.
Claim 1 identifies its subject matter nearly wholly functionally. Claim 1 is limited to an antibody or antigen-binding fragment thereof, meaning it is a protein. The remainder of the claim, however, describes the claimed antibody or antigen-binding fragment in terms of what it does. It is interpreted for this rejection as binding to at least K61 or K91 within the span of amino acids 46-101 within SEQ ID NO: 1. It also competes for binding to A56 with ten other antibodies identified by their CDR sequences, but there is no CDR sequence provided for the antibody/fragment actually being claimed. Finally, it binds A56 with particular KD, but the claim does not identify which structural aspects of the antibody/fragment are responsible for that binding. Applicants also nowhere provide, e.g., a sequence of any of the claimed antibodies.
The identification of conformational epitopes was unpredictable as of the effective filing date. Sanchez-Trincado et al. (2017, Journal of Immunology Research Article ID 2680160) teach that while a linear epitope can be predicted from the primary structure (sequence) of an antigen, prediction of conformational epitopes has “lagged behind” for two practical reasons. (Page 6, column 1; page 8, column 1; see Figure 5.) First, identifying a conformational epitope requires knowledge of the three-dimensional structure of an antigen second, isolating conformational B-cell epitopes from their protein context for selective antibody production is a difficult task that requires suitable scaffolds for epitope grafting. (Page 8, column 1.) Sanchez-Trincado writes that “prediction of conformational B-cell prediction is currently of little relevance for epitope vaccine design and antibody-based technologies.” (Page 8, column 1.) A diligent search of the prior and contemporaneous art revealed no three-dimensional structure for protein A56, so the methods described by Sanchez-Trincado would not have been available as of the effective filing date for the skilled artisan to have predicted the structure of any conformational epitope of A56.
Even if the conformational epitope of A56 were known, around the time of the invention, skilled artisans also recognized the unpredictable impact on antibody/CAR binding of changing amino acids within an epitope. See Michieli et al. (US 20200407452) at paragraphs 189, 194 (abrogation of antibody binding due to mutation of epitope within MET); Pantaleo et al. (US 20190062431) at paragraph 112 (abrogation of antibody binding due to mutation of epitope within PD-1). Indeed, some antibodies can distinguish between epitopes that differ by a single amino acid. See Kornete et al. (2018, Journal of Immunology 200: 2489-2501) at page 2493, column 2.
Under its broadest reasonable interpretation, claim 1 permits extensive variability within the conformational epitope because it requires that the antibody/fragment bind somewhere within a conformational epitope that itself consists of a 56-amino-acid portion of A56. The claim does not, however, require that the antibody/fragment bind to every amino acid in that stretch, and the as-filed specification does not support such an interpretation. All that is clearly required is that at least one nucleophilic amino acid within the antibody/fragment binds to either K61 or K91 within A56—and the fact that these two are presented as alternatives compels a conclusion that the antibody/fragment need not bind the entire 56-amino-acid portion.
For these reasons, skilled artisans did not recognize a structure-function correlation between an antibody/fragment’s structure and its ability to bind the conformational epitope encompassed by claim 1.
A review of the as-filed disclosure does not reveal such a structure-function correlation either. Applicants acquired antibodies to A56 through a commercial provider, then used phage-library techniques to assess A56 binding profiles. (Page 39, lines 10-24.) The disclosure is not specific about the nature or source of antibodies (e.g., polyclonal vs. monoclonal, source animal, etc.). The specification focuses on ten antibodies that have high specificity for A56. (Page 40, lines 14-21.) The specification explains that five antibodies—Ab13, Ab16, Ab18, Ab01, and Ab19—were used to identify epitopes on A56. (Page 41, lines 16-17.) The drawings show that these five antibodies do not bind the same portion of A56. Figures 45-491 are illustrative:
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It is clear from Figures 45-49 that the five antibodies applicants tested do not actually share a conformational epitope. The Figures also do not show any hydrogen bonds with K61 or K91. The specification discloses no information about the structure of these antibodies beyond the fact that they are antibodies of some sort. The as-filed disclosure therefore does not supply a sufficient structure-function correlation between a given antibody/fragment’s structure and its ability to bind the conformational epitope as it is set forth in claim 1.
“For inventions in emerging and unpredictable technologies, or for inventions characterized by factors not reasonably predictable which are known to one of ordinary skill in the art, more evidence is required to show possession.” MPEP 2163(II)(A)(3)(a)(ii). Disclosure of only a method of making the invention and the function may not be sufficient to support a product claim. Furthermore, the disclosure of a “newly characterized antigen” and a functional genus claim to corresponding binding molecules is insufficient to meet the description requirement. See Amgen Inc. v. Sanofi, 872 F.3d 1367, 1378 (Fed. Cir. 2017) (antibodies). The fact that making and using binding molecules with the claimed function might have been routine in the art might show an enabling disclosure but does not address possession. Id. (citing Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1345 (Fed. Cir. 2010) (en banc) (observing that written description and enablement are separate requirements of 35 U.S.C. 112)).
Claim 1 is not supported by adequate written description because the as-filed disclosure does not demonstrate possession of the invention as the claims recite it. Claims 4, 5, and 9-19 depend from claim 1 and do not rectify the issue, so they must also be rejected under 35 U.S.C. 112(a) for lack of written description.
Claims 1, 4, 5, and 9-19 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
This rejection is necessitated by the new requirement that a nucleophilic amino acid of the antibody or antigen-binding fragment forms a hydrogen bond with lysine at position 61 or 91 of protein A56 (SEQ ID NO: 1).
The factors to be considered in determining whether undue experimentation is required are summarized in In re Wands, 858 F.2d 731, 737, 8 U.S.P.Q.2d 1400, 1404 (Fed. Cir. 1988) (a) the breadth of the claims; (b) the nature of the invention; (c) the state of the prior art; (d) the level of one of ordinary skill; (e) the level of predictability in the art; (f) the amount of direction provided by the inventor; (g) the existence of working examples; and (h) the quantity of experimentation needed to make or use the invention based on the content of the disclosure. While all of these factors are considered, a sufficient number are discussed below so as to create a prima facie case.
Claim 1 is drawn to an antibody or antigen-binding fragment thereof that specifically binds to a conformational epitope of protein A56 (SEQ ID NO: 1). Specifically, a nucleophilic amino acid of claim 1’s antibody/fragment forms a hydrogen bond with lysine at position 61 or 91 of SEQ ID NO: 1. The as-filed disclosure does not provide a reproducible method for making such antibodies because the person of ordinary skill in the art would require undue experimentation to make and use the claimed antibody/fragment.
Preparation Example 3 (page 39 of as-filed specification) teaches that “[a] request for production of anti-A56 antibodies, which specifically bind to the protein A56, or a variant thereof, was made to Ybiologics.” The specification provides no details as to how these antibodies were generated or raised. A review of materials online at Y-Biologics reveals an “immune library screening” service in which a mouse is immunized with a designated target, then its spleen is lysed and mRNA extracted, which is then amplified by RT-PCR and cloned into an M13 phagemid. (See https://ybioservice.com/en/sub/service/antibody/antibody05.php, attached as reference U.) The Y-Biologics site describes the method at a high level of generality, giving no particular parameters for any of the steps (assuming this is in fact the service for which applicants relied on Y-Biologics).
Skilled artisans have long understood that the titer and characteristics of antibodies resulting from an immunization vary based on the method of raising them. (Asensio et al., 2004, MABS 11: 870-883; reference V; at page 870.) Skilled artisans also knew that the antibody repertoire from any given animal is shaped by both genetics (e.g., mouse strain) and antigen exposure. (Page 879, column 1.) Furthermore, antibodies derived from immune libraries are distinct from those derived from naïve libraries as the host's in vivo immune mechanisms shape the antibody repertoire to yield high affinity antibodies. (Lai and Lum, 2020, International Journal of Biological Macromolecules 163: 640-648; reference W; at abstract.) An infection-biased repertoire of an individual or host animal would also harbor remnants of antibodies against previously encountered antigens through memory B-cells, further complicating the unpredictability of generating a given desired set of antibodies by immunizing a host animal. (Page 643, column 1.) The repertoire of antibodies from a given host animal immunized under certain conditions would therefore have been expected to differ from the repertoire arising from a different protocol or host animal.
Applicant provides Example 5.1.2 starting at page 53 of the as-filed specification. In this experiment, applicant demonstrates that T52 of Ab13—a single antibody—binds protein A56’s K91 residue. (Page 54, lines 2-6.) Similar results are set forth for a few other antibodies. (Page 56, line 4; page 58, line 13; page 61, line 4; page 63, line 15.) There is no evidence, however, that a group of antibodies raised against A56 would necessarily include ones that hydrogen-bond to K61 or K91. The five exemplified antibodies do not inform the full scope of the claims.
In the context of this application, the fact that (presumably) a certain animal provided Ab13, Ab16, Ab18, Ab01, and Ab19 upon immunization with protein A56 under some unspecified conditions does not mean that a different animal would necessarily provide Ab13, Ab16, Ab18, Ab01, and Ab19 upon immunization with protein A56. The specification does not provide details of the immunization protocol (e.g., the mouse strain, the immunization schedule, etc.) such that the skilled artisan could generate Ab13, Ab16, Ab18, Ab01, and Ab19 without undue experimentation—much less that she could make other antibodies with the claimed hydrogen bonding. “Where the invention involves a biological material and words alone cannot sufficiently describe how to make and use the invention in a reproducible manner, access to the biological material may be necessary for the satisfaction of the statutory requirements for patentability under 35 U.S.C. 112.” See MPEP 2402. Applicants have not deposited the claimed antibodies or otherwise made them accessible to the public.
“When an invention relates to a new biological material, the material may not be reproducible even when detailed procedures and a complete taxonomic description are included in the specification.” In re Lundak, 773 F.2d 1216, 1220 (Fed. Cir. 1985). Here, the antibodies are novel, but the specification does not give any detail as to their manner of making other than identifying the commercial provider engaged by applicants to make them. As such, the antibodies are not reproducible, and the enablement requirement of 35 U.S.C. 112(a) is not met.
While a singular, narrow working embodiment cannot be a sole factor in determining enablement, its limited showing, in light of the unpredictable nature of the art and the lack of direction applicants present, provides additional weight to the lack of enablement in consideration of the Wands factors as a whole. Thus, one of ordinary skill in the art would not have a reasonable expectation of success in using the claimed invention. Claims 4, 5, and 9-19 depend from claim 1 and do not rectify the issue, so they must also be rejected under 35 U.S.C. 112(a) for lack of enablement.
Response to Arguments
Regarding the written-description rejection of record, applicant alleges that the five exemplified antibodies “recognize the same epitope on the A56 protein.” (Reply at 14.) The examiner disagrees. As indicated in the figures and reproduced above, each of the five exemplary antibodies binds a different, nonoverlapping subset of residues within A56. According to Figures 45-49:
Antibody
Residues of A56 bound by antibody
Ab13 (Fig. 45)
38, 46, 50, 70, 71, 75, 76, 78, 80, 84, 85
Ab16 (Fig. 46)
30, 33, 38, 45, 46, 55, 56, 58, 60
Ab18 (Fig. 47)
46, 50, 55, 56, 60, 71, 75, 76
Ab01 (Fig. 48)
30, 38, 45, 75, 84
Ab19 (Fig. 49)
45, 46
It is inaccurate to characterize these as the “same epitope.” The five exemplary antibodies appear to bind the same general area within A56, but they do not bind the same residues. The selection of “positions 46 to 101” in claim 1 also appears arbitrary because the residues implicated in binding by Figures 45-49 range from position 30 to position 85. None of the exemplary antibodies appear to bind residue 61 or residue 91, and claim 1 requires that at least one of these lysines is bound by the antibody/fragment. Applicant indicates at page 15 of the reply that T52 of Ab13 binds K61 within protein A56, but that binding is not reflected in Figure 45 as being part of the epitope for Ab13. Similar observations from Example 5 about the lysine-residue-binding properties of the exemplary antibodies are likewise incompatible with the depictions in Figures 45-49. Further explanation on this point is welcomed. See MPEP 716.02(b)(II).
Applicant alleges that CAR-T cells expressing the antigen-binding portions of the antibodies “exhibit superior anti-cancer efficacy,” which they allege supports a conclusion that the antibodies bind A56. (Pages 14-15.) The antibodies’ ability to bind A56 is not in dispute. The written-description requirement, however, asks about possession, i.e. the structure of the antibody/fragment applicants now claim.
Applicants explain that the “binning test” performed by BIACORE surface plasmon resonance was known and was actually performed on the five exemplary antibodies. (Reply at 15-16.) The skilled artisan’s ability to screen antibodies for binding to A56, however, does not address the fact that enablement and written description are two different requirements. It is noteworthy that the antibodies investigated in this application were made by Y-Biologics, which appears to be a commercial supplier of antibodies. (Specification at page 39.) Even if batches of commercially manufactured antibodies could be screened for A56 binding, doing so would not give any insight as to the structure of the antibodies themselves. The disclosure of a “newly characterized antigen”—here, a particular region within protein A56—and a functional genus claim to corresponding antibodies and fragments thereof is insufficient to meet the description requirement. See Amgen Inc. v. Sanofi, 872 F.3d 1367, 1378 (Fed. Cir. 2017).
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Lora E Barnhart Driscoll, whose telephone number is (571)272-1928. The examiner can normally be reached M-F 7:00-4:00 p.m. ET.
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/Lora E Barnhart Driscoll/ Primary Examiner, Art Unit 3991
1 For clarity, the examiner has replaced the reproductions of Figs. 45-49 with the more legible depictions provided in the replacement drawings.
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