Detailed Action
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 .
Claims 1-48 are cancelled.
Claims 49-65 are pending.
Applicant’s election of Group I, claims 49-62, in the reply filed on 10/28/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 63-65 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Groups, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/28/2025.
Applicant's election with traverse of a species of a TIGIT binding protein of claim 49 comprising a HC CDR1, HC CDR2, and HC CDR3 of SEQ ID NOs: 203-205, respectively, and a LC CDR1, LC CDR2 and LC CDR3 of SEQ ID NOs: 206-208, respectively, with an LCVR sequence of SEQ ID NO: 1861 and an HCVR sequence of SEQ ID NO: 1862, in the reply filed on 10/28/2025 as supplemented with the response filed by Applicant on 03/16/2026 is acknowledged. The elected CDR sequences of instant claims 49, 52-54, 56, 57, and 59-62 binding TIGIT are free from the prior art. The restriction requirement between an antigen-binding protein that binds CD112R and an antigen-binding protein that binds TIGIT, as set forth in the Office action mailed on 04/30/2025 and 01/15/2026, has been reconsidered in view of the allowability (subject to satisfactory resolution of the issues noted below in this Office Action) of claims to the elected species pursuant to MPEP § 821.04(a). The restriction requirement is hereby withdrawn as to any claim that requires all the limitations of an allowable claim. Specifically, the restriction requirement between the sequential species of antigen-binding proteins binding CD112R and antigen-binding proteins binding TIGIT presented in the 04/30/2025 and 01/15/2026 restriction requirements are withdrawn. The restriction requirement as to the Groups is preserved. Claims 50-51, 55, and 58, directed to antigen-binding proteins binding CD112R are no longer withdrawn from consideration because the claim(s) requires all the limitations of an allowable claim. However, claims 63-65, directed to nucleic acid products are withdrawn from consideration because the nucleic acid products are encompassed by a different group(s) and do not require the allowable matter as the nucleic acid sequence does not require the claimed amino acid sequences and a search for the amino acid sequences would not sufficiently account for the permissible degree of wobble in nucleic acid sequences so as to discern the allowability or lack thereof regarding the recited nucleic acid products.
In view of the above noted withdrawal of the restriction requirement, applicant is advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application.
Once a restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Claims 49-62 are under examination on the merits.
Priority
This application is a CON of US Patent NO. 11,919,953, filed 07/14/2021, which claims benefit of priority to US Provisional Application Nos. 63/052,011 and 63/212,315, filed 07/15/2020
and 06/18/2021, respectively.
IDS
The information disclosure statements (IDS) filed 06/27/2024, 03/16/2026, 06/17/2026, and 08/18/2026 have been considered.
Claim Rejections - 35 USC § 112
35 USC § 112(a)
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 49-62 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 claim(s) 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 purpose of the written description requirement is to ensure that the inventor had possession, at the time the invention was made, of the specific subject matter claimed. To satisfy the written description requirement, a patent 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. See, e.g., Moba, B. V. v. Dianwnd Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.
The Application claims a broad genus of antigen binding proteins (defined to encompass antibodies and antigen binding fragments thereof, such as 3 CDR fragments like VHHS; see for example, paragraph 0007 at page 2 of the instant specification) by impermissibly allowing variation within the CDRs without disclosure of a conserved structure/representative number of species to adequately describe said genus. The Application discloses antibodies against TIGIT/CD112R, where the embodiment of the antibody having 100% identity to CDR1-6 SEQ ID NOs: 203-204-205-206-207-208 is varied/mutated (see for example, Table A2 at page 24 of the instant specification for a total of 13 antibodies, the antibody of the parent US Patent NO. 11,919,953 and 12 variants; see also Table A1 at page 22 of the instant specification for a total of 15 antibodies, the antibody of the parent US Patent NO. 11,919,953 and 14 variants) and does not provide evidence that the claimed sequences with the claimed degree of mutations would function to bind as claimed. Therefore, in view of this disclosure, Applicant is claiming a broad genus of antigen binding proteins without a representative number of species of said genus. The specification does not provide adequate written description for the entire claimed genus of species of antibodies or of CDRs binding TIGIT/CD112R as claimed, because in the absence of empirical determination, one skilled in the art would be unable to immediately envision, recognize, or distinguish at least most of the members comprised within the genus claimed, specifically, which light and heavy chain CDR sequence combinations (bearing 1-4 mutations or 10% of varied residues per CDR) might be included in the genus.
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, reduction to drawings, 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. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. Applicant has only fully disclosed 1 set of 6 CDRs (1 species) for consideration with 12 variants (13 total antibodies binding TIGIT; see for example, table A2 at page 24 of the specification) binding TIGIT and 1 set of 6 CDRs (1 species) for consideration with 14 variants (14 total antibodies binding CD112R; see for example, table A1 at page 24 of the specification) binding CD112R. Thus, given the substantial antigen binding protein structure variation within the genus as well as the high level of unpredictability in the art, the disclosure of only 13 total species, 1 antibody having 100% homology and 12 variants with no known/demonstrated binding affinity for TIGIT, is not sufficiently representative of the entire genus claimed (encompassing CDRs not described or even invented and/or multiple combinations of mutations in the CDRs (up to 24 mutations across the 6 CDRs). Likewise the disclosure of only 15 total species, 1 antibody having 100% homology and 14 variants with no known/demonstrated binding affinity for CD112R, is not sufficiently representative of the entire genus claimed (encompassing CDRs not described or even invented and/or multiple combinations of mutations in the CDRs (up to 24 mutations across the 6 CDRs).
Furthermore, Applicant has not disclosed relevant, identifying characteristics of CDR region amino acid sequences that confer upon an antibody/ antigen binding protein the ability to function as claimed because the instant specification does not provide structural antigen binding protein features that correlate with a functional ability to bind as required by the claims.
Absent a clear description of the at least minimal structural features correlating with a functional ability to bind as claimed which are shared by members of a genus commonly sharing this function, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish which heavy and light chain CDR amino acid sequences may be mutated/varied/interchanged (such as interchangeability of the HCVR and LCVR, see exemplary instant claims 57-59) such that the resultant heavy and light chain variable regions comprise one or more sets of CDRs that confer the ability to function as claimed.
Furthermore, while the prior art teaches some understanding of the structural basis of antigen-antibody recognition, it is noted that the art is characterized by a high level of unpredictability, since the skilled artisan still cannot accurately and reliably predict the consequences of amino acid substitutions, insertions, and deletions in the antigen-binding domains. For example, Al Qaraghuli et al (2020, Nature Scientific Reports 10:13969), state that the six CDRs form a continuous surface to form the paratope that binds the epitope of the cognate antigen. This suggests that a change in the CDR sequence may result in a conformationally different paratope which may fail to bind target as claimed. Here, a mutation in the CDRs may result in a paratope unable to bind TIGIT/CD112R. Rabia et al (2018, Biochemical Engineering Journal 137:365-374) teach what effects mutations can have on an antibody's stability, solubility, binding affinity and binding specificity. Rabia et al report that an increase in antibody affinity can be associated with a decrease in stability (p. 366, col. 2 last paragraph; Fig. 2). Tiller et al (2017, J. Biol. Chem. (2017) 292(40) 16638–16652) and Tsuji et al (2022, J Virol 96:e00071-22) teach that mutations in the CDRs (especially HCDR3 are unpredictable and accompanied by tradeoffs in performance (for example increased affinity may lead to decreased specificity); see references in their entirety paying particular attention to the abstract of Tiller et al and the abstract and results section of Tsuji et al). CDR paratope structures have been revealed to be more complex than previously understood by Fernández-Quintero et al (Commun Biol 3, 589 (2020). https://doi.org/10.1038/s42003-020-01319-z; see for example, page 11) teaching that these paratopes are flexible and exist in multiple conformations in solution. Additionally, Piche-Nicholas et al (MAbs. 2018 Jan;10(1):81-94. doi: 10.1080/19420862.2017.1389355) teach that a large body of data exists demonstrating that neonatal Fc receptor (FcRn) binding of an IgG via its Fc CH2-CH3 interface trends with the pharmacokinetics (PK) of IgG. Through analysis of a broad collection of therapeutic antibodies containing more than 50 unique IgG molecules, Piche-Nicholas et al demonstrated that variable domains, and in particular complementarity-determining regions (CDRs), significantly alter binding affinity to FcRn in vitro. Furthermore, a panel of IgG molecules differing only by 1–5 mutations in CDRs altered binding affinity to FcRn in vitro, by up to 79-fold, and the affinity values correlated with calculated isoelectric point values of both variable domains and CDR-L3 (see for example, the abstract at page 81). Furthermore, Zhu et al (Protein Eng Des Sel. 2025 Jan 10;38:gzaf005. doi: 10.1093/protein/gzaf005) teach that the antibody variable domains (HCVR and LCVR), located at the tips of the Y structure, are responsible for antigen binding and consist of two beta sheets, which are stabilized by a conserved disulfide bond. These beta sheets are connected by loops, forming a total of six complementarity-determining regions (CDRs) that confer antigen specificity. The variable domains also include several beta strands that contribute to the structural framework (see for example, column 1 of page 2). Zhu et al further teach that it is widely recognized that not all CDR residues contribute equally to binding affinity, with some playing more critical roles than others. While the HCDR3 loop is the most dominant in binding, the distribution of other CDR loops involved in interactions appears to be more random and less predictable. Zhu et al further teach that framework residues, as their name implies, are essential for maintaining the overall structural integrity of antibodies (see for example, page 13). Zhu et al highlight that the state of the art, rather than closing in on predicting antibody structure-function correlation, is still grappling with and uncovering further complexity and unpredictability in antibody structure-function correlation.
The above cited references underscore the unpredictability of even a single mutation in the CDRs. The instant claims allow for mutations in the CDRs whereupon the mutated paratope may fail to bind TIGIT/CD112R, as claimed. Thus, the claims need to specify exact CDR sequences of the anti-TIGIT/anti-CD112R antigen binding protein. Alternatively, there must be evidence of a consensus sequence which, alone, is responsible predicably for target binding (a structure-function correlation) that binds TIGIT/CD112R, said consensus sequence being clearly amended into the claims as required.
Accordingly, absent empirical determination, one skilled in the art would be unable to predict or envision which CDR sequences comprised within the genus comprising the claimed CDR sequences may be combined/mutated such that the resultant antibody possesses an antigen-binding site capable functioning as claimed. The general knowledge and level of skill in the art does not adequately supplement the omitted description, because specific, not general guidance is needed. Since the disclosure fails to describe relevant, identifying structural characteristics, in the form of fixed heavy and light chain CDR amino acid sequence combinations, that correlate with the ability to function as claimed, and because the one disclosed species detailed above is not sufficient to describe the claimed genus, it is submitted that the written description requirement of 35 U.S.C. 112(a) has not been met.
The claims require an antigen binding protein that binds TIGIT/CD112R. The specification does not describe which amino acid residues of the antigen binding protein are responsible for the functions claimed. Rather, the specification implies that these antigen binding proteins must first be screened in an assay to ascertain if the antigen binding proteins have the TIGIT/CD112R-binding function required by the instant claims. Although the specification provides disclosure of 13 TIGIT-binding antibodies (1 parent and 12 variants)/15 CD112R-binding antibodies (1 parent and 14 variants), it fails to disclose the structures common to all members of the genus of antigen binding proteins encompassed by the broad definition provided by applicant. The specification does not disclose the structure of all of the claimed variant antigen binding proteins and fails to disclose which sequences are responsible for the functions claimed. In the absence of a known or disclosed correlation between structure and function, claims which encompass variants defined by their function are generally not considered described. There is significant variation without a clear consensus sequence between the parent antibody and the 12 variants, see the alignment provided below where the parent antibody having CDRs1-6 of SEQ ID NOs: 203-204-205-206-207-208 is identified in a red box.
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As can be seen in the alignments above, there is no clear consensus sequence across all of the claimed species of TIGIT binding proteins. Not a single residue is conserved in HCDR1, thus, there is no consensus region representing a structure-function correlation. Regarding HCDR2, only 2 residues are consistently conserved across the species and that conservation is not noted as required in the claim as drafted. Thus, even if there was an argument of a consensus region for HCDR2, that consensus region is not required by nor representative of the breadth of species encompassed by the claimed genus of antigen binding proteins. Regarding HCDR3, there is no single conserved residue among the disclosed or claimed species such that there is no consensus region clearly required by or representative of the species claims because there is no clearly demonstrated, unifying structure responsible for the claimed function of binding TIGIT. Additionally, a consensus sequence of only 2 non-consecutive residues the in only HCDR2 is not reasonably deemed to be a consensus sequence in light of the high degree of unpredictability regarding the binding function after CDR mutation as evidenced by the prior art cited in this rejection. Moreover, even where species of variants are shown, it is not clear that the mutations would function in isolation. Moreover, by the present claim drafting, the mutations can occur anywhere in the CDRs, not sparing any residue which could be argued to be conserved. A consensus sequence must be sufficient on its own to provide the function, however, at least the CDRs of antibodies, are highly sensitive to perturbations/mutations. The degree of permitted mutation across the CDRs has not been reasonably described by the presence of a consensus region (a unifying structure-function correlation demonstrated to be sufficient in and of itself for binding as claimed) or a representative number of species.
See additionally the alignment provided blow where the parent antibody having CDRs1-6 of SEQ ID NOs: 33-34-35-36-37-38 is identified in a red box.
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There is no clear consensus sequence across all of the claims species. As can be seen above, not a single residue is conserved in HCDR1, thus, there is no consensus region representing a structure-function correlation. Regarding HCDR2, only 1 residue is consistently conserved across the species and that conservation is not noted as required in the claim as drafted. Thus, even if there was an argument of a consensus region for HCDR2, that consensus region is not required by nor representative of the breadth of species encompassed by the claimed genus of antigen binding proteins. Regarding HCDR3, only 3 residues are consistently conserved across the species and that conservation is not noted as required in the claim as drafted. Thus, even if there was an argument of a consensus region for HCDR2, that consensus region is not required by nor representative of the breadth of species encompassed by the claimed genus of antigen because there is no clearly demonstrated, unifying structure responsible for the claimed function of binding CD112R. Taking a specific example, the Examiner will discuss the parent species (boxed in red) and the species directed above the boxed-in parent species. Even assuming that the variant (alignment O above) binds CD112R, it is unclear if the artisan can make the G->A mutation in HCDR2 without also making the S->T mutation in LCDR 2 and/or the
S->H mutation in LCDR3, to obtain a binding protein that binds CD112R? The state of the art supports that this would be highly unpredictable. Moreover, by the present claim drafting, the mutations can occur anywhere in the CDRs, not sparing any residue which could be argued to be conserved. For example, it is possible that the “O” variant in the alignment above only works when all three mutations are made and would fail if only one or two are made. In general, you CDRs are not interchangeable with predictability even from/in binding proteins that bind the same target. A consensus sequence, it must be sufficient on its own to provide the function. For the CDRs of antibodies, the state of the prior art supports a high degree of sensitive to mutations with unpredictable effects on binding. Additionally, a consensus sequence of only 1 residue in HCDR2 and/or 3 non-consecutive residues the in only HCDR3 is not reasonably deemed to be a consensus sequence in light of the high degree of unpredictability regarding the binding function after CDR mutation as evidenced by the prior art cited in this rejection. Furthermore, the mutations are permitted to occur anywhere in the CDR sequences as presently drafted.
Furthermore, there is no evidence presented that all of these antigen binding proteins bind target as claimed, let alone the other numerous variants encompassed by the claims.
As further evidence of the criticality of each and every CDR residue as well as the unpredictability of mutating/varying the CDRs, US8182813B2 (Amgen) discloses SEQ ID NO: 86 which meets the limitations of the instant claim 49 (1-4 amino acids per CDR may be varied) but for the fact that the sequence is tied to an antibody binding C-FMS, with no disclosure of binding to CD112R (see the alignment of Amgen’s SEQ ID NO:86 with instant SEQ ID NOS 33, 34, and 35, below).
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Moreover, the state of the prior art supports the unreliability of a consensus region for predictable target binding to a single target and for the unpredictability of interchanging HCDRs and LCDRs. For example, WO 2008068048 discloses an antibody with a heavy chain comprising three CDRs (SEQ ID NO: 2) that binds secreted aspartyl protease from Candida sp. US 20170355756 describes the same three CDRs in the heavy chain (C10-VH3) combined with a different light chain that binds human TDP-43. This is also highlighted when comparing the antibodies of US 20150196663 to those of US 20150266947. Both of the ‘633 and ‘947 publications screened for antibodies using the same library of antibodies (Sheet’s library; see for example ‘663 at paragraphs 59-69 and ‘947 at paragraph 131). The six CDRs of ‘947 SEQ ID NO: 11 (disclosed as binding Tau) and reference scFv15 (disclosed as binding the blood brain barrier, but not disclosed to bind Tau) are aligned below:
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The two antibodies share identical CDRs (e.g., CDR-L1), similar CDRs (e.g., CDR-H1, CDR-L2), and highly disparate CDR sequences (e.g., CDR-H3, CDR-L3). Clearly, a “consensus” sequence is insufficient to define the binding properties of an antibody. One could not envisage which portions of the CDRs are necessary to impart the claimed binding properties or which could be mutated without affecting such properties, nor does the instant specification provide guidance to this effect.
Applicant is directed to MPEP § 2163 for guidelines on compliance with the written description requirement. Here, applicant has not described a reasonable number of members of the genus of antibodies that would function in the method(s) as claimed, but rather has presented the public with an idea of how to perform an assay that might identify some peptides that fall within the scope of the claim. Of course, depending on what agents are used in the screening assay, it may well identify none. The Court of Appeals for the Federal Circuit addressed claims of this sort in great detail in University of Rochester v. G.D. Searle and Co. (69 USPQ 2nd 1886, CAFC 2004). In Rochester, the Federal Circuit upheld the district court's ruling that patent claims which recited administration of compounds not disclosed, but rather to be identified in a screening assay, were invalid on their face.
In Ariad, the court further noted that the written description plays a particularly important role in the biological arts, where patentees might otherwise be tempted to claim a genus of compounds by its function or result:
“The written description requirement also ensures that when a patent claims a genus by its function or result, the specification recites sufficient materials to accomplish that function—a problem that is particularly acute in the biological arts. 5 See Guidelines for Examination of Patent Applications Under the 35 U.S.C. 112, 1, “Written Description” Requirement, 66 Fed. Reg. 1099, 1105-1106 (Jan. 5, 2001). This situation arose not only in Eli Lilly but again in University of Rochester v. G.D. Searle & Co., Inc., 358 F.3d 916 [69 USPQ2d 1886] (Fed. Cir. 2004). In Rochester, we held invalid claims directed to a method of selectively inhibiting the COX-2 enzyme by administering a non-steroidal compound that selectively inhibits the COX-2 enzyme. Id. at 918. We reasoned that because the specification did not describe any specific compound capable of performing the claimed method and the skilled artisan would not be able to identify any such compound based on the specification's function description, the specification did not provide an adequate written description of the claimed invention. Id. at 927-28. Such claims merely recite a description of the problem to be solved while claiming all solutions to it and, as in Eli Lilly and Ariad's claims, cover any compound later actually invented and determined to fall within the claim's functional boundaries—leaving it to the pharmaceutical industry to complete an unfinished invention.”
Ariad Pharmaceuticals., Inc. v. Eli Lilly & Co., 94 USPQ2d 1161, 1173 (Fed. Cir. 2010) (en banc). Emphasis added.
The Federal Circuit has clarified Written Description as it applies to antibodies in the recent decision Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017). The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. 112(a) (or pre-AIA first paragraph) requires adequate written description of the antibody itself. Amgen, 872 F.3d at 1378-79. The Amgen court expressly stated that the so-called “newly characterized antigen” test, which had been based on an example in USPTO-issued training materials and was noted in dicta in several earlier Federal Circuit decisions, should not be used in determining whether there is adequate written description under 35 U.S.C. 112(a) for a claim drawn to an antibody. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the “newly characterized antigen” test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad, 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of an antigen alone is not considered adequate written description of a claimed antibody to that antigen, even when preparation of such an antibody is routine and conventional. Id.
While generically the structure of antibodies is known, the structure of the presently recited antibodies can vary substantially within the above given claimed recitations. As noted in Amgen, knowledge that an antibody binds to a particular epitope on an antigen tells one nothing at all about the structure of the antibody, wherein “instead of analogizing the antibody-antigen relationship to a ‘key in a lock,’ it [is] more apt to analogize it to a lock and ‘a ring with a million keys on it.” (Internal citations omitted). The relevant antibody art confirms this quandary, indicating that “knowledge of an epitope or antigen used to generate a monoclonal antibody is insufficient for making the original antibody available, even if suitable in vitro test systems for screening are used.” See p. 8, lines 3-5 of WO 2009/033743 A1. Therefore, those of skill in the art would not accept that the inventor had been in possession of the full genus of antibodies in the present claims.
Although screening techniques can be used to isolate CDR variant antibodies that possess the ability to function as claimed, Applicant is reminded that the written description requirement of 35 U.S.C. 112 is severable from the enablement provision. As stated in Vas-Cath Inc. v. Mahurkar (CA FC) 19 USPQ2d 1111, 935 F2d 1555, “The purpose of the 'written description' requirement is broader than to merely explain how to 'make and use'; the applicant must also convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed.”
Therefore, the antigen binding proteins, as claimed are only disclosed by function/insufficient structure, without a representative number of species or unifying, conserved structure clearly enabling one skilled in the art to readily envisage the members of the genus claimed which would function as claimed in the claimed method(s). Therefore, claims 49-62 are deemed to fail to meet the written description requirement, as presently drafted.
35 USC § 112(b)
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 57-59 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.
The claim drafting unduly obscures the scope of what is claimed and Applicant, as the drafter, is in the best position to clarify the scope of what Applicant intends to claim as the inventive concept.
Claims 54-59 fail to recite particular CDR sequences or to specify which numbering/annotation system (kabat, Chothia, AbM, etc.) is used to arrive at the recited CDRs of SEQ ID NOs: 1032 and 1033. Thereby, one artisan may view the claims as reciting CDRs encompassed by the kabat system and view CDRs noted under the IMGT system as non-infringing whereas another person skilled in the art may take the opposite view leading two persons skilled in the art to differ as to the reasonable interpretation of what is claimed and what infringes the metes and bounds of the claim as presently drafted. This is evidenced by Zhu et al (Protein Eng Des Sel. 2025 Jan 10;38:gzaf005. doi: 10.1093/protein/gzaf005), teaching that while the numbering schemes are known in the art, there are many various different CDR numbering schemes which arrive at different CDRs (see for example, Figure 2 comparing CDRs calculated by Kabat, IMGT, and AbM numbering schemes and page 2 bridging page 3 discussing the inconsistencies of aligning various numbering systems as a challenge for antibody engineering projects). Moreover, where sequence (such as SEQ ID NOS: 249, 250, 243, and 244 listed an non limiting examples, comprise variable residues (X), the landmarks for clear CDR annotation may be obscured, precluding the artisan from annotating the CDRs with a reasonable degree of confidence that the annotated CDRs align with the metes and bounds of the claim. Applicant, holding the CDRs out as the inventive aspect, is in the best position to clarify the scope of the CDRs for which patent protection is sought. Applicant’s assistance in this clarification would be appreciated to advance compact prosecution and promote clarity of the record. In light of the present claim drafting, artisans are left to dispute which CDRs, by which numbering system, are encompassed within the claim scope and would thereby infringe the claim.
Regarding claim 57 and its dependent claims 58 and 59, the independent claim 57 recites “An antigen-binding protein comprising a heavy chain comprising a HC CDR1, HC CDR2, HC CDR3 of any one of SEQ ID NOs: 29, 31, or 249, and a light chain comprising a LC CDR1, LC CDR2, and LC CDR3 of any one of SEQ ID NOs: 30, 32, and 250; or comprising a HC CDR1, HC CDR2, HC CDR3 of any one of SEQ ID NOs: 199, 201, or 243, and a light chain comprising a LC CDR1, LC CDR2, and LC CDR3 of any one of SEQ ID NOs: 200, 202, and 244”.
First, it is noted that SEQ ID NO: 249 has such a significant degree of variable residues, that the CDRs cannot be readily or reliably annotated by an artisan using common, art-known means such as Kabat or Chothia. Where the scope of the claim is unclear, Applicant bears the burden of clarifying the absolute metes and bounds of the claim for which patent protection is sought so as to put the artisan on notice as to what is protected from infringement.
Second, dependent claim 58 goes on to employ the same claim language of “wherein the heavy chain comprises the HC CDR1, HC CDR2, HC CDR3 of any one of SEQ ID NOs: 414…and the light chain comprises the LC CDR1, LC CDR2, and LC CDR3 of any one of SEQ ID NOs: 413…” such that the scope of the claim is unduly cumbersome and unclear. First, there is no proper antecedent basis for the HC CDR1, HC CDR2, HC CDR3 and/or LC CDR1, LC CDR2, and LC CDR3 recited. Therefore, it is unclear how the scope of this claim narrows the scope of claim 57 from which it depends because there is no readily ascertainable limitation that is further added unambiguously. For example, the CDRs of SQ ID NOs: 29, 31, of 249 are presumed to be present in all of the sequences recited as having the HCDR1-3 (HcCDR1, HC CDR2, HC CDR3) of SEQ ID NOs: 414…etc. However, that is all that is required by dependent claim 58. There is not expansion to require more that the CDRs of claim 57 while preserving proper claim dependency (such that the claim narrows the scope of the independent claim).
The same issues and problems apply to dependent claim 59 where the problematic language parallels the language noted in the rejection of claim 58, differing only with regard to the enumerated SEQ ID NOs.
Conclusion
No claim is allowed.
Notice:
The CDRs having 0-4 or 90% variation per CDR for:
HCDRs1-3 having SEQ ID NOs: 203-204-205 binding TIGIT as claimed;
LCDRs1-3 having SEQ ID NOs: 206-207-208 binding TIGIT as claimed; and
HCDRs1-3 having SEQ ID NOs: 33-34-35 binding CD112R as claimed,
have been searched and have been deemed to be free of the art (subject to the issues with the claims as set forth above).
While the prior art teaches some understanding of the structural basis of antigen-antibody recognition, it is noted that the art is characterized by a high level of unpredictability, since the skilled artisan still cannot accurately and reliably predict the consequences of amino acid substitutions, insertions, and deletions in the antigen-binding domains. For example, Al Qaraghuli et al (2020, Nature Scientific Reports 10:13969), state that the six CDRs form a continuous surface to form the paratope that binds the epitope of the cognate antigen. This suggests that a change in the CDR sequence may result in a conformationally different paratope which may fail to bind target as claimed. Here, a mutation in the CDRs may result in a paratope unable to bind TIGIT/CD112R. Rabia et al (2018, Biochemical Engineering Journal 137:365-374) teach what effects mutations can have on an antibody's stability, solubility, binding affinity and binding specificity. Rabia et al report that an increase in antibody affinity can be associated with a decrease in stability (p. 366, col. 2 last paragraph; Fig. 2). Tiller et al (2017, J. Biol. Chem. (2017) 292(40) 16638–16652) and Tsuji et al (2022, J Virol 96:e00071-22) teach that mutations in the CDRs (especially HCDR3 are unpredictable and accompanied by tradeoffs in performance (for example increased affinity may lead to decreased specificity); see references in their entirety paying particular attention to the abstract of Tiller et al and the abstract and results section of Tsuji et al). CDR paratope structures have been revealed to be more complex than previously understood by Fernández-Quintero et al (Commun Biol 3, 589 (2020). https://doi.org/10.1038/s42003-020-01319-z; see for example, page 11) teaching that these paratopes are flexible and exist in multiple conformations in solution. Additionally, Piche-Nicholas et al (MAbs. 2018 Jan;10(1):81-94. doi: 10.1080/19420862.2017.1389355) teach that a large body of data exists demonstrating that neonatal Fc receptor (FcRn) binding of an IgG via its Fc CH2-CH3 interface trends with the pharmacokinetics (PK) of IgG. Through analysis of a broad collection of therapeutic antibodies containing more than 50 unique IgG molecules, Piche-Nicholas et al demonstrated that variable domains, and in particular complementarity-determining regions (CDRs), significantly alter binding affinity to FcRn in vitro. Furthermore, a panel of IgG molecules differing only by 1–5 mutations in CDRs altered binding affinity to FcRn in vitro, by up to 79-fold, and the affinity values correlated with calculated isoelectric point values of both variable domains and CDR-L3 (see for example, the abstract at page 81).
The above cited references underscore the unpredictability of even a single mutation in the CDRs. The instant claims allow for mutations in the CDRs whereupon the mutated paratope may fail to bind TIGIT/CD112R, as claimed.
Furthermore, antibody-antigen binding is highly complex and unpredictable. Machine-learning models and in silico approaches generally remain unable to predict antigen-antibody binding, even when sifting between data sets of known antibodies and antigens to predict compatible binding and often produces incorrect models/pairings (see for example, Lowe, D. (Predicting Antibody Binding: No Champagne Just Yet, Science (2026); obtained from: http://www.science.org/content/blog-post/predicting-antibody-binding-no-champagne-just-yet). Underscoring the unpredictable state of the art, Subedy et al (bioRxiv 2026.01.17.700115; doi: https://doi.org/10.64898/2026.01.17.700115 (2026)) teach that achieving accurate predictions of complete antibody–antigen complexes is still an open challenge. Likewise, Spoendlin et al (Nat Mach Intell 7, 1755–1767 (2025). https://doi.org/10.1038/s42256-025-01131-6) teach that the flexibility of antibody complementarity-determining region (CDR) loops influences binding affinity and specificity, making it a key factor in understanding and designing antigen interactions, but predicting protein flexibility remains challenging, as current structure prediction tools struggle to capture multiple conformational states, particularly for antigen receptor CDRs. Therefore, prediction of the epitope to be bounds from the paratope structure or vice-a-versa is highly unpredictable.
The closest prior art is US20200040081 A1 (as cited in the nonfinal action for the parent Application No. 17/375,958 dated 02/27/2023; see exemplary paragraphs 0002 and 0016), which teaches CD112R binding proteins and TIGIT binding proteins, but does not reasonably suggest to the artisan the instantly claimed CDR sequences as binding CD112R or TIGIT with a reasonable expectation of success.
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/Ashley Gao/
Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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