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 .
Response to Amendment
Applicant’s amendment filed 07/24/2026 is acknowledged. Claims 7, 9, 11-14, 16, 17 and 19-21 are amended, claims 8 and 10 are newly canceled and claims 22 and 23 are new. Claims 7, 9 and 11-23 are under examination.
Sequence Rules
The amendment to the specification filed 07/24/2026 adds the sentence “The depicted sequence corresponds to SEQ ID NO: 129” at p. 3, line 12 in the description of Figure 1. Therefore, this application is now in compliance with the sequence rules,
Objections/Rejections Withdrawn
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Any previous objections or rejections over claims 8 and 10 are hereby withdrawn in response to Applicant’s cancelation of those claims.
Specification
The objection to the title of the invention as not being descriptive is withdrawn in response to Applicant’s amendment filed 07/24/2026 changing the title to: ANTI-LAG-3 SINGLE DOMAIN ANTIBODIES AND METHODS THERFOR.
Claim Objections
The objection to claim 11 for minor informalities is withdrawn in response to Applicant’s amendment correcting the grammatical error.
Claim Rejections - 35 USC § 112(b)
The rejection of claims 19-21 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn in response to Applicant’s amendment. Specifically, the claims are amended to recite “disease or disorder” and claim 21 no longer recites “cancers and tumors”.
Claim Rejections - 35 USC § 112(a) – Written Description
The rejection of claims 9, 13, 14 and 16 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112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is withdrawn in response to Applicant’s amendment. Specifically, claims 9 and 13 match the sequences to the corresponding CDRs (i.e., CDR1, CDR2 and CDR3) and claims 9, 13, 14 and 16 no longer recite 80% identity language.
Claim Rejections - 35 USC § 112(a) – Scope of Enablement
The rejection of claims 14 and 16 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, for scope of enablement is withdrawn in response to Applicant’s amendment. Specifically, claims 14 and 16 no longer recite 80% identity language.
Objection/Rejections Maintained
Claim Objections
Claims 14-17 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claim Rejections - 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.
Written Description
The rejection of claims 7, 11, 12 and 18-21 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 is maintained for reasons of record and the following. As noted above, the rejection of claims 9, 13, 14 and 16 is withdrawn. Claims 7, 11, 12 and 18-21 still encompass 36 possible CDRs selected from SEQ ID NOs: 4-7, 9-16, 23-24, 26-40 and 42-48, which results in at least 7,140 possible combinations that are not disclosed in the instant application. The rejection set forth at pages 6-10 of the Office action mailed 02/24/2026 is repeated herein:
The claims are drawn to huLAG-3 VHH (single domain antibodies) consisting of four framework region (FR) sequences and three complementarity determining region (CDR) sequences, wherein at least one of the CDR sequences has at least an 80% or 99% sequence identity with any one of SEQ ID NOs: 1-48. Claims 7, 8, 10-12 and 18-21 encompass three CDRs selected from SEQ ID NOs: 1-48 without any regard to whether the resulting VHH comprises a CDR1, CDR2 and CDR3 sequence, and therefore result in over 17,000 combinations VHH molecules not disclosed in the instant application. Further, claims 18-21 require the huLAG-3 VHH molecules have either pharmaceutical or diagnostic functions or both.
The CDR1 sequences are set forth in SEQ ID NOs: 1-16, CDR2 sequences are set forth in SEQ ID NOs: 17-32 and CDR3 sequences are set forth in SEQ ID NOs: 33-48. While claims 9 and 13 encompass VHH molecules with three CDRs selected from one of each of these groups, nevertheless, these still represent mix and match CDR selection resulting in over 4,000 VHH molecules not disclosed in the instant application. Regarding the four framework sequences, FR1, FR2, FR3 and FR4, claims 10-14 and 16 encompass framework regions, although claims 10-13 also take a mix and match approach to framework selection. Claims 14 and 16 each recite sequences encompassing the entire huLAG-3 VHH (i.e., SEQ ID NOs: 113-128), however, they require only 80% sequence identity to the recited sequences.
To provide evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered when analyzing claims for compliance with the written description requirement include: actual reduction to practice; disclosure of drawings or structural chemical formulas; sufficient relevant identifying characteristics (e.g., disclosure of complete or partial structure, physical and/or chemical properties, structure/function correlation); method of making the claimed invention; level of skill and knowledge in the art; and predictability in the art. See MPEP §2163.
With respect to antibodies, the Federal Circuit has clarified Written Description as it applies to antibodies in the 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 a newly characterized 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.
In deciding whether the application complies with the written description requirement of 35 USC 112(a) or 35 USC 112 (pre-AIA ), first paragraph, it is necessary to understand what Applicant has possession of and what Applicant is claiming. From the specification, it is clear that Applicant has possession of VHH molecules comprising the sequences set forth in instant SEQ ID NOs: 113-128 (see p. 14, Table 3 of the instant specification). While generically the structure of antibodies is known, the structure of the presently claimed antibodies can vary substantially within the above given claimed recitations. As noted above, claims 7-13 and 18-21 recite a mix and match approach to selecting CDRs and FR regions that result in over 17,000 undisclosed VHH molecules. Further, claims 7, 9, 10, 12-14, 16 and 18-21 encompass only 80% sequence identity to the recited sequences. Therefore, the claims encompass a large genus of possible huLAG-3 VHH molecules.
Regarding antibodies, the prior art teaches that small changes in the amino acid structure of the CDRs can have large effects on activity. For instance, Piche-Nicholas et al. (MAbs. 2018; 10: 81-94. doi: 10.1080/19420862.2017.1389355) teach that the “binding affinity of IgG molecules…to FcRn that differed by only a few amino acid residues in CDRs revealed that small changes in CDRs, as minute as one amino acid residue change, could alter affinity to FcRn up to 79-fold.” See p. 89, right column, last paragraph of Piche-Nicholas et al. Further, while it is recognized that an antibody can be described by its CDRs, the art also teaches that that even a single amino acid substitution in a framework region can result in dramatic changes in activity (see Liang et al., Scientific Reports (2021)11: 22365, especially, paragraph bridging pages 6-7). The specification does not disclose a representative number of species capable of describing the claimed genus of over 17,000 VHH molecules. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states that “applicant must 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.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116). With the exception of SEQ ID NOs: 113-128, the skilled artisan cannot envision the detailed chemical structure of the encompassed VHH molecules, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence. Therefore, only isolated polypeptides comprising the amino acid sequence set forth in SEQ ID NOs: 113-128, but not the full breadth of the claim meets the written description provision of 35 U.S.C. §112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
Response to Arguments
Applicant argues case law at pages 10 and 12, with which the examiner has no issue. Applicant argues at p. 11 that the framework regions have been amended to recite 95% sequence identity and that the specification provides support (pages 7-11 and 14) for the recited CDR sequences.
This argument has been fully considered but is not found persuasive. The formation of an intact antigen-binding site on the VHH requires three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the CDRs are critical in maintaining the antigen binding specificity and affinity. While the specification describes the 36 CDRs recited in claim 7, Applicant does not have possession of the thousands of VHH antibodies encompassed by claim 7 and its dependents. The MPEP provides guidance regarding antibodies at MPEP 2163(II)(A)(3)(a):
The claimed invention itself must be adequately described in the written disclosure and/or the drawings. For example, disclosure of an antigen fully characterized by its structure, formula, chemical name, physical properties, or deposit in a public depository does not, without more, provide an adequate written description of an antibody claimed by its binding affinity to that antigen, even when preparation of such an antibody is routine and conventional. See Amgen Inc. v. Sanofi, 872 F.3d 1367, 1378, 124 USPQ2d 1354, 1361 (Fed. Cir. 2017)(“knowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies”); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1351-52, 97 USPQ2d 1870, 1877 (Fed. Cir. 2011) (patent disclosed the antigen the claimed antibody was supposed to bind, but did not disclose any antibodies with the specific claimed properties).
Scope of Enablement
The rejection of claims 7, 9, 11-13 and 18-21 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph for scope of enablement is maintained for reasons of record and the following. As noted above, the rejection of claims 14 and 16 is withdrawn. Claims 7, 11, 12 and 18-21 still encompass 36 possible CDRs selected from SEQ ID NOs: 4-7, 9-16, 23-24, 26-40 and 42-48, which results in at least 7,140 possible combinations that are not disclosed in the instant application. The disclosed utility of claims 7, 9, 11-13 and 18 is as a pharmaceutical for diagnosing or treating disease and claims 19-21 are drawn to methods comprising diagnosing or treating disease with the claimed VHH antibodies. The specification discloses that mere binding to an antigen is not sufficient to provide enablement for these utilities: “[t]he ability of VHHs to block the interaction of human LAG-3 and its canonical ligand HLA-DR is not predictive for their therapeutic efficacy” (see p. 24), thus suggesting that only Nb 3150 (SEQ ID NO: 113) has potential benefit in cancer co-treatment. The rejection set forth at pages 10-15 of the Office action mailed 02/24/2026 is repeated herein:
The claims are broad with respect to the recited huLAG-3 VHH molecules. The claims recite huLAG-3 VHH (single domain antibodies) consisting of four framework region (FR) sequences and three complementarity determining region (CDR) sequences, wherein at least one of the CDR sequences has at least an 80% or 99% sequence identity with any one of SEQ ID NOs: 1-48. Claims 7, 8, 10-12 and 18-21 encompass three CDRs selected from SEQ ID NOs: 1-48 without any regard to whether the resulting VHH comprises a CDR1, CDR2 and CDR3 sequence, which results in over 17,000 VHH molecules. Claim 18 recites a pharmaceutical composition comprising a huLAG-3 VHH according to claim 7 and claims 19-21 encompass diagnosing or treating diseases/disorders associated with an overexpression of huLAG-3 comprising administering the huLAG-3 VHH according to claim 7. The CDR1 sequences are set forth in SEQ ID NOs: 1-16, CDR2 sequences are set forth in SEQ ID NOs: 17-32 and CDR3 sequences are set forth in SEQ ID NOs: 33-48. While claims 9 and 13 encompass VHH molecules with three CDRs selected from one of each of these groups, they still represent mix and match CDR selection resulting in over 4,000 VHH molecules. Regarding the four framework sequences, FR1, FR2, FR3 and FR4, claims 10-14 and 16 encompass framework regions, although claims 10-13 also take a mix and match approach to framework selection. Claims 14 and 16 each recite sequences encompassing the entire huLAG-3 VHH (i.e., SEQ ID NOs: 113-128), however, they require only 80% sequence identity to the recited sequences.
The instant specification discloses that radiolabeled mouse LAG-3 VHH molecules (moLAG-3) “positively correlate[d] with the percentage of LAG-3+ tumor-infiltrating immune cells in different tumor models” (see p. 21, lines 14-32, Figure 1). Further, treatment of a mouse model with PD-1 inhibitors resulted in “upregulation of mouse LAG-3 on MC38 tumor-infiltrating immune cells but not in immunological organs” (see pages 21-22, Figures 2-3). In addition, a moLAG-3 antibody increased the “antitumor activity” of PD-1 inhibition in a mouse model (see pages 22-23, Figure 4). These studies provide evidence in a mouse model that the moLAG-3 antibody may be useful as a cotreatment in cancer therapy.
The specification discloses the development of specific human LAG-3 VHH molecules (see p. 23, Figures 5-6), which were tested in vitro for their ability to block human LAG-3 interaction with HLA-DR (its ligand) and for therapeutic efficiency. The huLAG-3 VHH molecules denoted as 3150 (SEQ ID NO: 113), 3185 (SEQ ID NO: 125), 3187 (SEQ ID NO: 119) and 3194 (SEQ ID NO: 126) were capable of blocking huLAG-3/HLA-DR binding (see p. 24, Figure 7B), although only 3150 was capable of activating huLAG-3+ 2D3 cells (see p. 24, Figure 7D). This 2D3 cell-based assay is described in Versteven et al. (Oncotarget, 2018, Vol. 9, (No. 45), pp: 27797-27808—on IDS filed 12/22/2023). The specification concludes that “[t]he ability of VHHs to block the interaction of human LAG-3 and its canonical ligand HLA-DR is not predictive for their therapeutic efficacy”, thus providing evidence that Nb 3150 (SEQ ID NO: 113) has potential benefit in cancer co-treatment. Claims 7-13 and 18-21 recite a mix and match approach to selecting CDRs and FR regions. Further, claims 7, 9, 10, 12-14, 16 and 18-21 encompass only 80% sequence identity to the recited sequences. Therefore, the claims encompass many possible huLAG-3 VHH molecules while the evidence only shows that a limited number have the required binding and activation capability. In addition to treatment, claims 19-21 encompass diagnosis comprising administering a huLAG-3 according to claim 7. Nevertheless, the claims provide no steps as to how to diagnose disease using the claimed huLAG-3 VHH molecules. Therefore, the evidence provided in the instant specification is not commensurate with the breadth of the claims.
The number of mutations generally possible in any given protein that can be made with a reasonable expectation of success are limited. Certain positions in the sequence are critical to the protein's structure/function relationship, e.g., such as various sites or regions directly involved in binding, activity and in providing the correct three-dimensional spatial orientation of binding and active sites. Regarding antibodies, the art teaches that small changes in the amino acid structure of the CDRs can have large effects on activity. For instance, Piche-Nicholas et al. (cited above) teach that the “binding affinity of IgG Molecules…to FcRn that differed by only a few amino acid residues in CDRs revealed that small changes in CDRs, as minute as one amino acid residue change, could alter affinity to FcRn up to 79-fold.” See p. 89, right column, last paragraph of Piche-Nicholas et al. Further, while it is recognized that an antibody can be described by its CDRs, the art also teaches that that even a single amino acid substitution in a framework region can result in dramatic changes in activity (see Liang et al., cited above; especially, paragraph bridging pages 6-7).
Although machine learning algorithms have improved the ability to predict protein 3D structure from sequences, methods based on artificial intelligence for predicting the impact of mutations on protein stability still face challenges, including prediction biases towards “generalization”, “data set”, “destabilizing mutations” and the inability to predict the effects of multiple mutations. See Figure 1, at p. 162 and the discussion at pages 165-166 of Pucci et al. (Current Opinion in Structural Biology 2022, 72: 161-168). Even in the case of single mutations, artificial intelligence programs do not accurately “predict the impact of mutation on protein stability” or function (see p. 2, 2nd paragraph and p. 7, 1st full paragraph of Pak et al., PLoS ONE 18(3): e0282689. https://doi.org/10.1371/journal.pone.0282689). In the instant case, the claims encompass VHH molecules with up to a 20% divergence from the recited sequences. Applicants have provided little or no guidance beyond the mere presentation of sequence data to enable one of ordinary skill in the art to determine, without undue experimentation, the positions which are tolerant to change by amino acid substitutions or deletions, and the nature and extent of changes that can be made in these positions. Although the specification outlines art-recognized procedures for producing and screening for active VHH molecules, this is not adequate guidance as to the nature of active derivatives that may be constructed, but is merely an invitation to the artisan to use the current invention as a starting point for further experimentation.
Due to the large quantity of experimentation necessary to test the extremely large genus of VHH molecules for the ability to bind LAG-3 as well as diagnose and treat disease, the lack of direction/guidance presented in the specification regarding the same, the absence of working examples directed to the same, the complex nature of the invention, the unpredictability of the effects of mutation on protein structure and function, and the breadth of the claims which fail to recite limitations on the VHH molecules, the diseases treated and how to diagnose said diseases, undue experimentation would be required of the skilled artisan to make and/or use the claimed invention in its full scope.
Response to Arguments
Applicant argues at pages 13-16 that the claims are not broad, the level of skill in the art is high, that there is express guidance for the claimed CDR and FR sequences, and the quantity of experimentation is not undue.
This argument has been fully considered but is not found persuasive. Claim 7 and its dependents are broad because they encompass thousands of VHH antibodies. Further, when evaluating claims for enablement, it is appropriate to consider the disclosed utility of the claimed molecules, which in this case is diagnosing and treating a host of diseases or disorders. The specification discloses that the huLAG-3 VHH molecules denoted as 3150 (SEQ ID NO: 113), 3185 (SEQ ID NO: 125), 3187 (SEQ ID NO: 119) and 3194 (SEQ ID NO: 126) were capable of blocking huLAG-3/HLA-DR binding (see p. 24, Figure 7B), although only 3150 was capable of activating huLAG-3+ 2D3 cells (see p. 24, Figure 7D). The specification concludes that “[t]he ability of VHHs to block the interaction of human LAG-3 and its canonical ligand HLA-DR is not predictive for their therapeutic efficacy” (see p. 24). The evidence provided in the specification is not commensurate in scope with the breadth of the claims. Due to the large quantity of experimentation necessary to test the extremely large genus of VHH molecules for the ability to bind LAG-3 as well as diagnose and treat disease, the lack of direction/guidance presented in the specification regarding the same, the absence of working examples directed to the same, the complex nature of the invention, the unpredictability of the effects of mutation on protein structure and function, and the breadth of the claims which fail to recite limitations on the VHH molecules, the diseases treated and how to diagnose said diseases, undue experimentation would be required of the skilled artisan to make and/or use the claimed invention in its full scope.
Conclusion
Claims 7, 9, 11-13 and 18-21 are rejected, claims 14-17 are objected to and claims 22 and 23 are allowed.
THIS ACTION IS MADE FINAL. 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 CHRISTINA M BORGEEST whose telephone number is (571)272-4482. The examiner can normally be reached M-F 9-5:30 EDT.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Stucker can be reached at 5712720911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/CHRISTINA M BORGEEST/Primary Examiner, Art Unit 1675
Prosecution Insights