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 .
Election/Restrictions
1. The Election filed July 23, 2026, in response to the Office Action of January 27, 2026, is acknowledged and has been entered. Applicants elected without traverse Group I and the species of an antigen-binding site that binds PD-L1 comprising a heavy and light chain variable region comprising a CDR1, CDR2, and CDR3 of SEQ ID NOs: 11, 12, 89, 47, 48, and 49. Claims 1, 3, 5, 7, 11, 19, 22, 27, 29, 31-32, 34, 38-39, 41, 43, 49, 52, 59, 64, 69, 77, 79-82, 89, and 91 are pending. Claims 27, 29, 31-32, 34, 38-39, 41, 43, 49, 52, 59, 64, 69, and 77 have been withdrawn from further consideration by the examiner under 35 CFR 1.142(b) as being drawn to non-elected inventions. Claims 1, 3, 5, 7, 11, 19, 22, 79-82, 89, and 91 are currently under prosecution as drawn to the elected species.
Priority
2. Application claims the benefit and priority of PCT/US2022/013417 filed on 1/21/2022, which claims the benefit of provisional application 63/140,749 filed on 1/21/2021. Priority is granted to 63/140,749 and the effective filing date of 1/21/2021.
Claim Objections
3. Claim 1 is objected to because of the following informalities: in claim 1a, line 5 a space is omitted in the phrase “aCDR2 sequence”. Appropriate correction is required.
Claims 7 and 22 are objected to because of the following informalities: in claim 7 section (a) line 1 and claim 22 section (a) line 1 the recitation “an KD”. Appropriate correction is required.
Claim 82 is objected to because of the following informalities: line 1 recites “a pharmaceutical composition comprising the an antigen-binding site”. Appropriate correction is required.
Claim Interpretation
4. The examiner’s broadest reasonable interpretation of the claims is set forth below.
Claim 1 recites:
“An antigen-binding site that binds PD-L1, comprising: (a) a heavy chain variable region (VH) comprising a complementarity determining region 1 (CDR1) sequence, a complementarity determining region 2 (CDR2) sequence, and a complementarity determining region (CDR3) sequence of SEQ ID NOS: 11, 12, and 89, respectively; and a light chain variable region (VL) comprising a CDR1 sequence, a CDR2 sequence, and a CDR3 sequence of SEQ ID NOS: 47, 48, and 49, respectively,”
The phrases “a CDR1 sequence, a CDR2 sequence, and a CDR3 sequence of SEQ ID NOs: 11, 12, and 89, respectively” and “a CDR1 sequence, a CDR2 sequence, and a CDR3 sequence of SEQ ID NOs: 47, 48, and 49, respectively,” are reasonably interpreted as an antigen-binding site comprising a VH and VL region comprising a CDR1, CDR2, and CDR3 comprising any sequence found in the corresponding SEQ ID NOs, as few as two consecutive amino acids long.
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.
5. Claims 11, 19, and 22 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.
Claim 11 recites “A protein comprising the antigen-binding site of claim 1, optionally wherein the protein comprises one or more antibody heavy chain constant regions, further optionally wherein:”. The use of the word “optionally” indicates that the limitation following may or may not be present meaning the limitation is not required. It is unclear what further limitations are required for the metes and boundaries of the claims to be satisfied. For the sake of compact prosecution, the examiner will consider the first optionally to not be present making the recitation of “the protein comprising one or more antibody heavy chain constant regions” as a required limitation of the claim.
Claim 11 also recites in section (d) “the antibody heavy chain constant region comprises, relative to SEQ ID NO:90, one or more mutations selected from L234A, L235A, P329G, Y349C, S354C, T366S, T366W, L368A, F405K, K409A and Y407V,” and in section (f) “the protein comprises a first antibody heavy chain constant region
comprising, relative to SEQ ID NO:90, one or more mutations selected from S354C,
T366W and K409A and a second antibody heavy chain constant region comprising, relative to SEQ ID NO:90, one or more mutations selected from Y349C, T366S, L368A,
F405K and Y407V,”. These limitations are unclear because SEQ ID NO: 90 has 227 amino acid sequences so it is unclear what the mutations being relative to SEQ ID NO: 90 are and where the mutations are located.
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.
7. Claims 1, 3, 5, 7, 11, 19, 22, 79-82, 89 and 91 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. This is a WRITTEN DESCRIPTION rejection.
The claims are drawn to an antigen-binding site that binds PD-L1, comprising a heavy chain variable region (VH) comprising a complementarity determining region 1 (CDR1) sequence, a CDR2 sequence, and a CDR3 sequence of SEQ ID NOs: 11, 12, and 89, respectively; and a light chain variable region (VL) comprising a CDR1 sequence, a CDR2 sequence, and a CDR3 sequence of SEQ ID NOs: 47, 48, and 49, respectively.
Thus, the claims identify the antigen-binding site by the function of binding PD-L1, and a partial sequence structure that comprises a VH comprising a CDR1, CDR2, and CDR3 with any amino acid sequences as few as two consecutive amino acids as set forth in SEQ ID NOs: 11, 12, and 89, respectively; and a VL comprising a CDR1, CDR2, and CDR3 with any amino acid sequences as few as two consecutive amino acids as set forth in SEQ ID NOs: 47, 48, and 49, respectively. Thus the claims encompass a vast genus of antigen-binding site variants comprising variable VH regions comprising variable CDR1, CDR2, and CDR3 sequences, and variable VL regions comprising variable CDR1, CDR2, and CDR3 sequences required to bind PD-L1.
The instant specification discloses seventeen structurally distinct antigen binding sites that bind PD-L1 as described in Table 1 on pages 25-29 with distinct CDR sequences for each antigen-binding site structure. The instant specification distinctly identifies a heavy chain variable domain comprising six structurally distinct CDR1 sequences, seven structurally distinct CDR2 sequences, and fifteen structurally distinct CDR3 sequences, and a light chain variable domain comprising eight structurally distinct CDR1 sequences, ten structurally distinct CDR2, and nine structurally distinct CDR3 sequences.
Thus, the instant specification identifies seventeen structurally distinct antigen-binding sites that comprise specific structurally distinct CDR1, CDR2, and CDR3 sequences for both VH and a VL binding domains that all function to bind PD-L1. The specification fails to disclose any other sequence variants having as few as two consecutive amino acids found in SEQ ID NOs: 11, 12, 89, 47, 48, or 49 that possess the function of binding PD-L1.
To provide adequate written description and evidence of possession of the claimed antigen-binding site genus, the instant specification can structurally describe representative VH and VL binding domains comprising CDR variants that function to bind PD-L1, or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.). A disclosure that does not adequately describe a product itself logically cannot adequately describe a method of using that product.
In this case, the only factor present in the claims is a recitation of the antigen-binding site function, “binds PD-L1”, and partial sequence structure as stated above. The instant specification fails to describe structural features common to the members of the antigen-binding site genus, which features constitute a substantial portion of the genus because the instant specification fails to disclose representative antigen-binding site variant sequences that function as claimed. A definition by function does not suffice to define the genus because it is only an indication of what the antigen-binding site does, rather than what it is. Other than for the antigen binding sites disclosed in Table 1, the specification fails to provide the VH and VL binding domains comprising CDR1, CDR2, and CDR3 structural features coupled to the claimed functional characteristics. The instant specification fails to describe a representative number of antigen-binding site sequence variants for the genus of antigen-binding sites that function as claimed. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus required to make the claimed antigen-binding sites.
The claims broadly encompass an antigen-binding site comprising a VH and a VL binding domain with any sequence variant having as few as two amino acids from CDR1, CDR2, and CDR3 SEQ ID NOs: 11, 12, 89, 47, 48, and 49 that functions to bind PD-L1. Applicants have not established any reasonable structure-function correlation with regards to the sequences in the CDRs that can be altered and still maintain PD-L1 binding function. Sela-Culang et al. (Frontiers in Immunol., 2013, 4:302), teaches that CDRs have a unique set of contact preferences, favoring certain amino acids over others. (See Sela-Culang, pgs. 5-6). Given the well-known high level of polymorphism of antigen-binding CDR sequences and structure, the skilled artisan would not have been in possession of the vast repertoire of antibodies encompassed by the claimed invention. One could not reasonably or predictably extrapolate the structure of a single antigen-binding site comprising a VH and VL comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 11, 12, 89, 47, 48, and 49 to the structure of any variants required to bind PD-L1 as broadly claimed. Therefore, one could not readily envision members of the broadly claimed genus.
Although Applicants may argue that it is possible to screen for antigen-binding sites that bind PD-L1 and function as claimed, the court found in (Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004) that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. “As we held in Lilly, “[a]n adequate written description of a DNA … ‘requires a precise definition, such as by structure, formula, chemical name, or physical properties,’ not a mere wish or plan for obtaining the claimed chemical invention.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions.” Knowledge of screening methods provides no information about the structure of any future antigen-binding sites yet to be discovered that may function as claimed. The PD-L1 antigen provides no information about the structure of an antigen-binding site that binds to it.
Given the lack of representative examples to support the full scope of the claimed variant antigen-binding sites, and lack of reasonable structure-function correlation with regards to the unknown variable sequences in the CDRs that provide PD-L1-binding function, the present claims lack adequate written description. Thus, the specification does not provide an adequate written description of antigen-binding site variants that bind PD-L1 and comprise a VH and VL with as few as two defined consecutive amino acids in each CDR from SEQ ID NOs: 11, 12, 89, 47, 48, and 49 that is required to practice the claimed invention.
Examiner Suggestion: Examiner suggests amending claim 1 to recite:
“An antigen-binding site that binds PD-L1, comprising:
(a) a heavy chain variable region (VH) comprising a complementarity determining region 1 (CDR1) sequence, a complementarity determining region 2 (CDR2) sequence, and a complementarity determining region (CDR3) sequence of the amino acid sequences of SEQ ID NOS: 11, 12, and 89, respectively; and a light chain variable region (VL) comprising a CDR1 sequence, aCDR2 sequence, and a CDR3 sequence of the amino acid sequences of SEQ ID NOS: 47, 48, and 49, respectively.”
Prior Art
8. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Philips et al. (International Immunol., 2015, 27(1):39-46), discloses the use of monoclonal antibodies against PD-L1 as a method for treating cancer. (See Philips, abstract). Specifically, Philips discloses preclinical studies of pharmaceutical compositions using PD-L1 antibodies that compete for binding with PD-1, a co-inhibitory molecule of T cells, and neutralization of the PD-L1 ligand by antibodies modulates the immune response in the tumor microenvironment through CD8+ T cell activity including IFN-γ production leading to the inhibition of tumor cell growth and effective treatment of cancer including melanoma and pancreatic cancer. (See Phillips, pg. 40 “The PD-1 Signaling Pathway in the Immune Response” and pgs. 42-43 “PD-L1-Targeting Strategies”).
Phillips is not cited as prior art because it does not disclose any antigen-binding sites with a heavy chain variable region (VH) and a light chain variable region (VL) comprising CDR sequences of SEQ ID NOs: 11, 12, 89, 47, 48, and 49.
Conclusion
9. Claims 1, 3, 5, 7, 11, 19, 22, 79-82, 89, and 91 are rejected.
10. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LINDSAY DUNN whose telephone number is (571)272-5825. The examiner can normally be reached Monday-Friday 8-4:30.
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, Samira Jean-Louis can be reached at 571-270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/LINDSAY DUNN/Examiner, Art Unit 1642
/Laura B Goddard/Primary Examiner, Art Unit 1642
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