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 Status
Claim(s) 1-18 is/are currently pending and presented for examination on the merits.
Priority
Acknowledgment is made of applicant's claim for foreign priority based on an application filed in China on 08Mar2021. It is noted, however, that applicant has not filed a certified copy of the CN 202110250342.9 application as required by 37 CFR 1.55.
Specification
The use of trade name(s) or mark(s) used in commerce (e.g., BioLegend, BD, GE Healthcare, Miltenyi, Thermo Scientific, BD FACSCelesta), has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Interpretation
Claims 3 and 4 are drawn to an antibody or antigen binding fragment comprising “at least one amino acid substitution” in both the heavy and light chains. The broadest reasonable interpretation of these limitations is that there is no limit on the number of amino acid substitutions in the heavy and light chains, and therefore the entire antibody may be substituted for any other antibody.
Claim Objections
Claim 2 (and claims 6, 13) is objected to because of the following informalities: claim 2(1)-(4) have no joining word, there should be an “and” between 2(3) and 2(4). Appropriate correction is required.
Claim 3 (and claims 4, 7-8, 14-15) is objected to because of the following informalities:
“selected from at least one of” in line 1 should be “selected from
Claim 3(1)-(4) have no joining word, there should be an “and” between 2(3) and 2(4).
Appropriate correction is required.
Claim 16 is objected to because of the following informalities: “antibody for cancer therapy other than (1)” should be “an additional antibody for cancer therapy, wherein the additional antibody is different than the antibody of claim 1. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of 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.
Claim(s) 16 is/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.
Regarding claim 16, the phrase “(1)” in line 4 is not defined in the terms preceding it. Thus, the phrase “(1)” renders the claim indefinite because it is unclear whether the limitation(s) in the parentheses are a part of the claimed invention. See MPEP 2173.05(d). It is unclear if “(1)” is a limitation or merely provided as an example. To promote compact prosecution, the phrase “(1)” is not considered a limitation of the claim(s). This rejection may be overcome by amending claim(s) 16 to clearly recite the claimed invention.
Claim Rejections - 35 USC § 112(a)
Claim(s) 1, 3-5, 7-12, and 14-18 is/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.
Claimed Invention
Claim(s) 1, 3-5, 7-12, 14-18, are drawn to an antibody that binds PVRIG antigen.
Breadth of Claims
Further, claim(s) 1, 5, 9-12, 16-18, are drawn to a mix and match of heavy and light chain domains. Specifically, the inventions as disclosed in claim(s) 1 (and claims 5, 9-12, 16-18) recite(s) “…wherein HCDR1 is selected from a sequence set forth in [SEQ ID NOs: 52-24]…wherein HCDR2 is selected from a sequence set forth in [SEQ ID NOs: 55-58]…wherein HCDR3 is selected from a sequence set forth in [SEQ ID NOs: 59-61]…wherein LCDR1 is selected from a sequence set forth in [SEQ ID NOs: 62-63]…wherein LCDR2 is selected from GAS or YAS; and wherein LCDR3 is selected from [SEQ ID NOs: 64-66]”. These claims read that one would be able to mix and match HCDR1-3 and LCDR1-3 domains and arrive at an antibody that binds to PVRIG antigen. However, according to Applicant’s disclosure there are specific 6 CDR (e.g., HCDR1-3 and LCDR1-3) SEQ ID pairings for each antibody (see summary table below for ease of review). One of ordinary skill in the art would understand that to mix and match the HCDR1-3 and LCDR1-3 sequences must be identical. An example alignment of the each of the HCDR1-3 domains claimed show that they comprise different sequences (see below).
Alignment of instant anti-PVRIG HCDR1-3 (SEQ ID NOs: 52, 55, 59 for Ab1 | 53, 56, 60 for Ab2 | 53, 57, 60 for Ab3 | 54, 58, 61 for Ab4)
CLUSTAL O(1.2.4) multiple sequence alignment
Ab1_SeqIDs_52xxx55xxx59 GYTFSSFSxxxILPGSNSTxxx---SSYW-----FAY 29
Ab2_SeqIDs_53xxx56xxx60 GYTFSTFAxxxILPGINNTxxx---STYW-----FAY 29
Ab3_SeqIDs_53xxx57xxx60 GYTFSTFAxxxILPGGNNTxxx---STYW-----FAY 29
Ab4_SeqIDs_54xxx58xxx61 GYSFTAYTxxxINPYNGGTxxxAREGNYYGSRGDFDY 37
**:*::::**** * ..**** ..*: * *
The invention as disclosed in claim(s) 3 (and claims 7, 14) recite(s) “…heavy chain variable region…having at least one amino acid substitution compare to [the VH sequence(s)]…light chain variable region…having at least one amino acid substitution compared to [the VL sequence(s)]…” in claim 3(1)-(5); and claim(s) 4 (and claims 8, 15) recite(s) “…wherein an amino acid sequence of the heavy chain…having at least one amino acid substitution compared to [the HC sequence(s)]….and wherein an amino acid sequence of the light chain…having at least one amino acid substitution compared to [the LC sequence(s)]…” in lines 6 and 10. A skilled artisan would understand that a conventional antibody heavy chain (HC) comprises a heavy chain variable region (VH) comprising HCDR1-3, and a light chain (LC) comprises a light chain variable region (VL) comprising LCDR1-3. Therefore, the claim(s) encompass a genus of heavy and/or light chain variable regions comprising variability (e.g., at least one amino acid substitution), in the heavy and/or light chain variable regions which are claimed as having the function of specifically binding to PVRIG antigen. This means that the variability in sequence identity can also occur in the CDRs, the domains that are critical for the antibody binding to its target, which one of ordinary skill in the art would understand to result in unpredictable binding characteristics with no reasonable expectation of maintaining PVRIG antigen binding. Additionally, the instant disclosure does not provide a structure-function correlation that would allow for a person of ordinary skill in the art to envision what variation can occur to the light and heavy chains, particularly in the CDR regions, such that the obtained structure would result in the claimed functions.
Scope of Disclosed Species
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The anti-PVRIG antibodies in the Applicant disclosure (see summary table above for details) with 100% sequence identity in the CDR regions of both the heavy and light chain variable regions represents the anti-PVRIG antibodies that the applicant was in possession of at the time of filing.
State of the Prior Art
At the time of filing, antibody functionality was 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 substitutions (e.g., mix and match of CDRs, residue mutations) to CDRs is unpredictable and that each construct requires function testing.
Sela-Culang, Kunik, and Ofran (Fron. Immuno., Vol. 4, Article 302, Oct. 2013), hereinafter “Sela-Culang”, 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 [e.g., 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 [e.g., pg. 1, “The Motivations for…”].
Further, Herold et al. (Nature Scientific Reports, 7:12276, 25 Sep 2017), hereinafter “Herold”, 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” [e.g., pg. 14, ¶ 2]. Further, Herold asserts that multiple determinants regulate antigen affinity and the interactions with CDRs are complex [e.g., pg. 14, ¶ 3].
At the time of filing, US 2021/0069241 A1 (hereinafter “US241”) taught anti-CD112R antibodies as anti-cancer therapies [e.g., title, abstract], and that CD112R is also called “PVRIG” [e.g., ¶ 0015]. US241 taught various separate species of anti-CD112R antibodies [e.g., tbl. 2]. Therefore, the prior art demonstrates that the binding of CD112R (also known as PVRIG) is possible by various anti-CD112R antibodies. The prior art does not teach a known structure activity relationship for HCDR1-3 and LCDR1-3 in an anti-PVRIG (anti-CD112R) antibody that would allow prediction of all of the possible combinations of CDR residues that would specifically bind to PVRIG antigen.
Thus, making changes to the complete six CDR sequence (e.g., CDR mix and matching, CDR residue substitutions) 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 all of the possible 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 CDRs may be exchanged (e.g., mix and matched), or which CDR residues may be changed (e.g., substituted) and still result in an antibody that binds PVRIG. 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) 1, 3, and 4 would need to recite the specific 6 CDR set (e.g., HCDR1-3 and LCDR1-3) for each anti-PVRIG antibody of the instant claim(s), without variability in the CDR sequences thereof. Claims 5, 7-12, 14, and 16-18 can overcome this rejection by amending claims 1, 3, and 4 as described above.
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(s) 3-4, 7-8, and 14-15 is/are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature (natural phenomenon) without significantly more.
Claims 3-4, 7-8, and 14-15 are evaluated using the “Subject Matter Eligibility Test for Products and Processes” flow chart as shown in MPEP § 2106 (III).
Step 1: Is the claim to a process, machine, manufacture or composition of matter?
Yes. The claim is drawn to a composition of matter which is one of the four statutory categories.
Step 2A, Prong One: Does the claim recite an abstract idea, law of nature, or natural phenomenon?
Yes. The claims are directed towards the natural phenomenon of ”an antibody”.
Step 2A, Prong Two: Does the claim recite additional elements that integrate the judicial exception into a practical application?
No. While claim(s) 3 and 4 recite specific SEQ ID NOs corresponding to antibodies or antigen binding fragments thereof, claims 3 and 4 also recites “at least on amino acid substitution” in relation to each recited antibody sequence without a limit on the number of substitutions thereof. Further, the claim(s) do require specific antigen binding. Therefor any antibody (e.g., those naturally occurring) will meet the limitations of claims 3 and 4. Given the above, these claims do not integrate a judicial exception into a practical application.
Step 2B: Does the claim recite additional elements that amount to significantly more than the judicial exception?
No. The judicial exception is recited without additional limitations amounting to significantly more than the exception. As stated above, the broadest reasonable interpretation of instant claims 3 and 4 includes any antibody, including those naturally occurring. This does not amount to significantly more than the judicial exception.
Claim(s) 7-8 and 14-15, which require the antibody of either claim 3 or 4, act to further limit by including (1) isolatable nucleic acids encoding the instant claimed antibody (e.g., a natural phenomenon), or (2) a pharmaceutical composition comprising the instant claimed antibody and a pharmaceutically acceptable carrier (e.g., whole blood comprising antibodies and sodium bicarbonate). These limitations do not amount to significantly more than the judicial exception.
As the instant claims 3-4, 7-8, and 14-15 recite judicial exceptions and claim a population antibodies, nucleic acids and/or pharmaceutical compositions for which the judicial exception is not integrated into a practical application, and no elements that amount to significantly more than the judicial exception are recited, the claims were found not to be drawn to eligible subject matter under 35 USC § 101.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim(s) 3-4, 7-8, and 14-15 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US 2021/0069241 A1 (hereinafter “A241”).
Regarding instant claim(s) 3-4, US241 teaches ant-TIGIT and anti-CD112R antibodies [e.g., title, abstract; tbls. 1-2].
Regarding instant claim(s) 7-8, US241 further teaches nucleic acids encoding the anti-TIGIT or anti-CD112R antibodies [e.g., ¶ 0035-0042].
Regarding instant claim(s) 14-15, US241 further teaches a pharmaceutical composition comprising an inhibitor of TIGIT or CD112R (e.g., an anti-TIGIT or anti-CD112R antibody) and a pharmaceutically acceptable carrier [e.g., ¶ 0152-0187].
Free From the Prior Art
During the course of examination, the anti-PVRIG antibodies comprising an antigen binding domain comprising (1) HCDR1-3 and LCDR1-3; (2) VH and VL; and/or (3) HC and LC, as indicated in the summary table below, were found to be nonobvious over the prior art. Briefly, a sequence search of the prior art returned no 100% matches to either of the instant claimed HCDR1-3 and/or VH sequences, and therefore would not return any 100% matches to any of the instant claimed HC sequences (see closest prior art alignments below).
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Alignment of anti-PVRIG murine antibody 1 HCDR1-3 (SEQ ID NO: 52, 55, 59) with WO2012175691-A1 (Mouse anti-Axl mab (20G7-D9) heavy chain variable region, SEQ: 1):
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Alignment of anti-PVRIG murine antibody 2 HCDR1-3 (SEQ ID NO: 53, 56, 60) with CN111548412-A (Anti-HBsAg monoclonal antibody VH, SEQ ID 15):
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Alignment of anti-PVRIG murine antibody 3 HCDR1-3 (SEQ ID NO: 53, 57, 60) with WO2022187968-A1 (Anti-LILRB1 antibody 4G5 VH region, SEQ ID 49):
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Alignment of anti-PVRIG murine antibody 4 HCDR1-3 (SEQ ID NO: 54, 58, 61) with WO2010022737-A1 (Mouse anti-CD5 antibody VH sequence, SEQ ID 401):
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Alignment of anti-PVRIG humanized antibody 4-hu1 VH (SEQ ID NO: 3) with WO2015089449-A2 (Human SC34.28 humanized antibody variable heavy chain clone, SEQ 207):
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Alignment of anti-PVRIG humanized antibody 4-hu2 VH (SEQ ID NO: 6) with WO2015089449-A2 (Human SC34.28 humanized antibody variable heavy chain clone, SEQ 207):
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Alignment of anti-PVRIG humanized antibody 4-hu3 VH (SEQ ID NO: 9) with WO2015089449-A2 (Human SC34.28 humanized antibody variable heavy chain clone, SEQ 207):
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Alignment of anti-PVRIG humanized antibody 4-hu4 VH (SEQ ID NO: 12) with WO2015089449-A2 (Human SC34.28 humanized antibody variable heavy chain clone, SEQ 207):
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Alignment of anti-PVRIG humanized antibody 4-hu5 VH (SEQ ID NO: 15) with GB2406094-A (huHMFG1 (scFv/clone 4.9) amino acid sequence):
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Alignment of anti-PVRIG humanized antibody 4-hu6 VH (SEQ ID NO: 18) with GB2406094-A (huHMFG1 (scFv/clone 4.9) amino acid sequence):
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Alignment of anti-PVRIG humanized antibody 4-hu7 VH (SEQ ID NO: 21) with WO2019232503-A1 (Anti-Integrin B7 scFv antibody VH region, SEQ 4200):
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Alignment of anti-PVRIG humanized antibody 4-hu8 VH (SEQ ID NO: 24) with WO2019232503-A1 (Anti-Integrin B7 scFv antibody VH region, SEQ 4200):
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Alignment of anti-PVRIG humanized antibody 4-hu9 VH (SEQ ID NO: 27) with WO2019232503-A1 (Anti-Integrin B7 scFv antibody VH region, SEQ 4200):
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Alignment of anti-PVRIG humanized antibody 4-hu10 VH (SEQ ID NO: 30) with GB2406094-A (huHMFG1 (scFv/clone 4.9) amino acid sequence):
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Alignment of anti-PVRIG humanized antibody 4-hu11 VH (SEQ ID NO: 33) with GB2406094-A (huHMFG1 (scFv/clone 4.9) amino acid sequence):
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Conclusion
No claims are currently allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMY M CHATTIN whose telephone number is (571)270-0646. The examiner can normally be reached T-F 0600-1600 PST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu can be reached at (571) 272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/AMY M. CHATTIN/Examiner, Art Unit 1643
/GARY B NICKOL/Primary Examiner, Art Unit 1643