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 .
Priority
The instant application, filed 02/19/2024, is a 371 filing of PCT/EP2022/073195, filed 08/19/2022, and claims foreign priority to application GB21111905.2, filed 08/19/2021 from Great Britain. A certified copy of foreign priority was provided.
Status of Claims/Application
The preliminary amendment of 02/19/2024 is acknowledged. Claims 1-41 are canceled and claims 42-65 are newly added. Claims 42-65, filed on 02/14/2024 are currently pending and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 02/19/2024, 07/11/2024, 07/18/2025, and 04/27/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
Claim Objections
Claim 46 is objected to because of the following informalities: Claim 46 recites “IgG1LALAGA” which should be IgG1 LALAGA for better clarity. Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 65 is rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. Claim 65 is drawn to a method of diagnosing cancer but the step is to use the antibody of claim 42. The claim does not fall within at least one of the four categories of patent eligible subject matter because the claims are directed to the “use” of the antibody. The claims are not directed toward a: 1) composition of matter; 2) machine; 3) manufacture; or 4) process, but rather a “use” of a composition of the conjugate, wherein no active method steps are present to suggest a process is being claimed. "Use" claims that do not purport to claim a process, machine, manufacture, or composition of matter fail to comply with 35 U.S.C. 101 MPEP 2173.05(q).
Claim Rejections - 35 USC § 112
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.
Claim 65 is 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.
As described prior in the rejection under USC 101 for claim 65, the metes and bounds of the claim is also indefinite wherein the antibody is claimed “for use”. MPEP 2173.05(q) states attempts to claim a process without setting forth any steps involved in the process generally raises an issue of indefiniteness. Recitation of a use without any active, positive steps delimiting how this use is actually practiced is indefinite.
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.
Claim 54 is 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.
Claimed Invention
Claim 54 is drawn to an antibody that cross-competes with the antibody of claim 42 for binding to HLA-G or binds to an epitope of HLA-G comprising V194, F195, Y197, E198, Q224, Q226, D227, V248, V249, P250, and Y257 of HLA-G (SEQ ID NO: 107).
Breadth of Claims
The invention as disclosed in claim recites “…an antibody that cross-competes with the antibody of claim 47 for binding to HLA-G”. A genus of species is not present in the instant specification or prior art that would demonstrate a structure activity relationship would be known for antibody CDR residues for the recited function of binding the protein target HLA-G that would cross-compete with the antibody of claim 42 and bind to epitopes of HLA-G as defined above. There is a lack of an appropriate number of species with identical or alternative amino acid residues within the CDR binding determinant region that indicate which amino acid residues: i) are essential for binding; ii) can be changed and still allow protein target binding; iii) disrupt protein target binding; or iv) alter antibody secretion. One of skill in the art would reasonably conclude that applicant was not in possession of the required genus of CDR claims 54 of the antibody at the time of filing.
Scope of disclosed species
The anti-HLA-G antibodies in the Applicant disclosure (page 155-177, Table 36) with 100% sequence identity in the CDR regions of the heavy and light chain variable regions recited in claim 42 represents the anti-HLA-G antibodies that the applicant was in possession of at the time of filing.
However, the antibody that would cross-compete with the antibody of claim 42 is not in the specification.
State of the Prior Art
At the time of filing, antibody functionality were known to depend on the entire structure, particularly a full complement of six CDRs. It is understood by one of ordinary skill in the art that that mutation to CDRs is unpredictable and that each construct requires function testing.
Sela-Culang (Sela-Culang I, Kunik V and Ofran Y (2013) The Structural Basis of Antibody-Antigen Recognition. Front. Immunol. 4:302. doi: 10.3389/fimmu.2013.00302) reviews the structural basis of antibody-antigen recognition in the state of the art. Naturally occurring antibodies have six hypervariable loops are commonly termed complementary determining regions (CDRs) and are widely assumed to be responsible for antigen recognition (pg. 1, abstract; pg. 3, “The Role of CDRs and their Definition”). A person of ordinary skill in the art would understand that although the above basics of antibody-antigen binding are known, that the specifics of antibody structure (e.g., within the CDRs) that underlie the antigen recognition are not well characterized (pg. 1, “The Motivations for…”).
Further, Herold (Herold, E.M., John, C., Weber, B. et al. Determinants of the assembly and function of antibody variable domains. Sci Rep 7, 12276 (2017). https://doi.org/10.1038/s41598-017-12519-9) teaches that it should be emphasized that there is no correlation between experimentally determined change in antibody binding affinity and a given mutation and additionally that no such correlation is expected because antigen binding is “affected by each CDR loop differently” and changes thereto “can in principle affect antigen binding affinity in an unpredictable way” (pg. 14, paragraph 2). Further, Herold asserts that multiple determinants regulate antigen affinity and the interactions with CDRs are complex (pg. 14, paragraph 3)
At the time of filing, Attia (Attia JVD, Dessens CE, van de Water R, Houvast RD, Kuppen PJK, Krijgsman D. The Molecular and Functional Characteristics of HLA-G and the Interaction with Its Receptors: Where to Intervene for Cancer Immunotherapy? Int J Mol Sci. 2020 Nov 17;21(22):8678. doi: 10.3390/ijms21228678. PMID: 33213057; PMCID: PMC7698525.; hereinafter “Attia”) taught anti-HLA-G antibodies were recognized in the art as a promising therapeutic for cancer (page 1, title). Attia taught various separate species of anti-HLA-G antibodies (page 10, Table 2) and discloses that the majority of the available antibodies only recognize one or two isoforms of HLA-G and in order to abrogate the function of HLA-G in cancer, all isoforms of HLA-G expressed by tumor cells have to be inhibited (page 10, paragraph 1, 5. HLA-G as Target for immune checkpoint inhibition in Cancer, “Firstly, the majority of the available antibodies only recognize one or two isoforms of HLA-G “ and “Therefore, inhibition of all HLA-G isoforms expressed by tumor cells is crucial to abrogate the full function of HLA-G in cancer “). Therefore, the prior art demonstrates that the binding of HLA-G is possible by various anti-HLA-G antibodies. The prior art does not teach a known structure activity relationship for HCDR1-3 and LCDR1-3 in anti-HLA-G antibody that would allow prediction of CDR residues that specifically bind to one HLA-G antigen.
Thus, making changes to the CDR sequence of an antibody sequence is a highly unpredictable process and one skilled in the art could not a priori make any predications regarding such mutations with any reasonable expectation of success nor envisage the breadth of structurally unrelated CDR combinations that would still possess the required function(s).
Conclusion
As indicated by the art, a full complement of 6 CDRs are required for antigen binding and one cannot predict which CDR residues may be changed and still result in an antibody that binds X. Written description can be met if the claims recite the minimal structure that is needed to perform the function recited in the claims. Above, the art indicates that the 6 CDRs in an antibody antigen-binding domain are the minimal structure that binds to a target antigen. Specifically, Applicant claim(s) # would need to recite the 6 CDRs in the antibody that bind X antigen, without variability in the sequences thereof.
Conclusion
Allowable Subject Matter
Claim 42 contains SEQ ID NOs: 1-3 and 4-6 that correspond to light chain and heavy chain CDRs of an antibody that specifically bind to HLA-G which is free of the prior art. Accordingly, a polynucleotide that encodes for the said light chain variable and heavy chain variable CDRs in claim 56 is free of the prior art. As allowable subject matter has been indicated, applicant's reply must either comply with all formal requirements or specifically traverse each requirement not complied with. See 37 CFR 1.111(b) and MPEP § 707.07(a). Specifically, claim 46 is objected to, claim 56 is rejected under U.S.C. §112(a)- written description, and claim 65 is rejected under U.S.C. §101 Subject matter eligibility.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Lam Thuy Vi Tran Ho whose telephone number is (571)272-9135. The examiner can normally be reached Monday-Friday 7:30-3.
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/LAM THUY VI TRAN HO/Examiner, Art Unit 1647 /L.T./Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
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