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 .
DETAILED ACTION
Election/Restrictions
Applicant’s election without traverse of group 1, a Chimeric Antigen Receptor (CAR) with species, an antibody of claim 1-(i), CD28 as a transmembrane domain and as intracellular costimulatory domain, in the reply filed on 1/20/2026 is acknowledged.
Claims 2, 4-6, 8-10. 12-14, 19, 24, 29-30, 32-48, 50, and 53-54 have been cancelled.
Claims 1, 3, 7, 11, 15-18, 20-23, 25-28, 31, 49, and 51-52 are pending.
Claims 7, 11, 49 and 51-52 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and species (claims 7 and 11), there being no allowable generic or linking claim.
Claims 1, 3, 15-18, 20-23, 25-28, and 31, drawn to a chimeric antigen receptor (CAR) comprising antigen binding domain to p95HER2 (elect claim 1-(i)), a transmembrane domain, an intracellular signaling domain and/or costimulatory domain, are examined on merits.
Information Disclosure Statement
The information disclosure statement (s) (IDS) submitted on 5/17/2023 are/is considered by the examiner and initialed copies/copy of the PTO-1449 are/is enclosed.
Sequence Requirement
A first office action can be performed on this application, however, this application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 C.F.R. § 1.821(a)(1) and (a)(2). This application fails to comply with the requirements of 37 C.F.R. §§ 1.821-1.825.
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings, figures 11-12, are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Applicant is reminded to check the entire disclosure to ensure that the application is in sequence compliance.
Applicant is given three months from the date of the letter within which to comply with the sequence rule.
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 22 recites the limitation "wherein the hinge regions is the CD8 hinge domain, in claim 1. There is insufficient antecedent basis for this limitation in the claim because claim 1 does not contain the recitation or limitation of hinge region in the CAR. Clarification is required.
The lack of clarity could arise where a claim refers to “said lever” or “the lever,” where the claim contains no earlier recitation or limitation of a lever and where it would be unclear as to what element the limitation was making reference. Similarly, if two different levers are recited earlier in the claim, the recitation of “said lever” in the same or subsequent claim would be unclear where it is uncertain which of the two levers was intended (See MPEP 2173.05).
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:
VH and VL CDR1-3 or functionally equivalent variants and
Mixed and Matched VH and VL between two antibodies
Claims 1, 3, 15-18, 20-23, 25-28, and 31 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
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. Possession may be shown. For claimed product the specification must provide sufficient distinguishing identifying characteristics of the genus, including disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, level of skill and knowledge in the art, and predictability in the art or any combination thereof.
The claims are broadly drawn to Chimeric Antigen Receptor (CAR) comprising the antibody binding to p95HER2 comprising
Claim is drawn to
A chimeric antigen receptor (CAR) comprising:
(i) an antigen-binding domain specific for p95HER2,
(ii) a transmembrane domain and
(iii) at least one intracellular signaling domain and/or costimulatory domain wherein the antigen-binding domain is selected from the group consisting of: (i) an ScFv (ScFv1) characterized in that: - the framework regions of the VL and VH regions are humanized,
the CDR1, CDR2 and CDR3 of the VH region comprise, respectively, the sequences of SEQ ID NO: 1, 2 and 3 or functionally equivalent variants thereof or the sequences of SEQ ID NO: 1, 174 and 3 or functionally equivalent variants thereof, and
- the CDR1, CDR2 and CDR3 of the VL region comprise respectively, the sequences of SEQ ID NO: 4, 5, and 6 or functionally equivalent variants thereof or the sequences of SEQ ID NO: 175, 5 and 6 or functionally equivalent variants thereof…….
Claim 31 is drawn to
An scFv or antigen binding fragment thereof comprising the same
CDR1, CDR2 and CDR3 of the VH region comprise, respectively, the sequences of SEQ ID NO: 1, 2 and 3 or functionally equivalent variants thereof or the sequences of SEQ ID NO: 1, 174 and 3 or functionally equivalent variants thereof, and
- the CDR1, CDR2 and CDR3 of the VL region comprise respectively, the sequences of SEQ ID NO: 4, 5, and 6 or functionally equivalent variants thereof or the sequences of SEQ ID NO: 175, 5 and 6 or functionally equivalent variants thereof.
The claim further recites the frameworks sequences.
Thus, the claims encompass 1) functional equivalent variants of antigen binding domain from each of the VH and VL domain and 2) Mixed and Matched VH and VL between the two antibodies.
The specification teaches the invention relates to a Chimeric Antigen Receptor (CAR) capable to targeting p95HER2-expressing cells, wherein the CAR comprises anti-p95HER2 antibody or antigen binding fragment comprising scFv (abstract, figure 1-2). The specification teaches a few structures of CARs comprising sequences of different p95HER2 antibodies as well as the domains of TM, hinge, linker……(figure 11-12). Regarding with claimed anti-p95HER2 antibodies set forth claim 1-(i), application teaches the antigen binding fragment to p95HER2 being scFv1 that characterized in that:
[0127] the VL and VH regions are humanized,
[0128] the CDR1, CDR2 and CDR3 of the VH region comprise, respectively, the sequences of SEQ ID NO: 1, 2 and 3 or functionally equivalent variants thereof OR the sequences of SEQ ID NO: 1, 174 and 3 or functionally equivalent variants thereof, and
[0129] the CDR1 CDR2 and CDR3 of the V L region comprise respectively, the sequences of SEQ ID NO: 4, 5, and 6 or functionally equivalent variants thereof OR the sequences of SEQ ID NO: 175, 5 and 6 or functionally equivalent variants thereof.
Thus, first, the application does not teach or describe where and which amino acid alternations to form a VH or VL that considered as a functionally equivalent variants. The application des not teach or suggest any species of the antibody that are considered as a functionally equivalent variant.
Second, as set forth in the claim 1-(i), the application describes two different VH domains that could be randomly paired to two different VL domains, which could potentially form Mixed and Matched VH and VL, e.g VH having the VHCDR1-3 of sequences of SEQ ID NOs; 1, 2, and 3 paired to the VL domain having the sequences of SEQ ID NOs 4, 5, and 6 as VLCDR1-3, while the VHCDR1-3 of sequences of SEQ ID NOs; 1, 2, and 3 can be also paired to the VL domain having the VLCDR1-3 sequence of SEQ ID NOs: 175, 5 and 6. Such mixed and matched VH and VL has no correlation between the structures of the antibodies and their claimed function, p95HER2 binding. The application does not provide detailed teaching or description for such pairs of the VH and VL for claimed function.
It is well known, the CDRs, VL/VH and scFv contain the critical amino acids for the antigen recognition and affinity of binding, even one amino acid change within the CDRs could result in antibody having different affinity or even binding to totally different antigens as compared to the parent antibody. When VHCDR sequences are mixed and matched, the CDR1, CDR2 and/or CDR3 sequence from a particular VH sequence is replaced with a structurally similar but different CDR sequence(s). Thus, it will be readily apparent to the ordinarily skilled artisan that novel VH and VL sequences are created by substituting one or more VHCDR and/or VLCDR region sequences with structurally similar but different sequences from the CDR sequences for the antibodies as claimed. While the claims, as written, require alternations (variation) the amino acids in CDRs, or VH/VL or scFv. One skilled in the art would not know how to match the amino acids used for p95HER2 protein binding without undue quadrative experimentations.
Thus, the specification as recited in the claims describes VH and VL of the antibodies binding to protein p95HER2, but provides improper description for the claimed antibodies with mixed and matched in VLs/VHs and scFvs in sequences as there is no correlation between the structure of the antibodies and their claimed function, p93HER protein binding.
Therefore, only the anti-p93HER2 antibody, or antigen binding fragment thereof including scFv for CAR comprising VH domain having the VHCDR1-3 sequences of SEQ ID NOs, 1, 2 and 3 paired to VL domain having the VLCDR1-3 sequences of SEQ ID NOs: 4, 5 and 6 as one antibody OR the VH domain having the VHCDR1-3 sequences of SEQ ID NOs, 1,174, and 3 paired to the VL domain having the VLCDR1-3 sequences of SEQ ID NOs:174, 5 and 6 as another antibody in the claimed CAR , but not antigen binding fragment written as claimed, meet 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).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
The applied reference has a common inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Claim 1, 15-18, 20-23, and 25-28 is/are rejected under 35 U.S.C. 103 as being unpatentable over Klein et al (US20180118849, published May 2018) as evidenced by sequence alignment in view of Fan et al (US20180230225, published Aug. 2018).
In this rejection, the claimed antibody is examined to the extent of VHCDR1-3 having the sequence of SEQ ID NOs: 1, 2, and 3 respectively and VLCDR1-3 having the sequence of SEQ ID NOs: 4, 5 and 6 respectively (see QY search below).
Klein et al teach anti-p95HER2 antibody or antigen binding fragment comprising the heavy chain variable domain VHCDR1-3 and light chain variable domain VL-CDR1-3 that have the identical VHCDR1-3 of SEQ ID Nos 1, 2 and 3 and VLCDR1-3 of SEQ ID NOs: 4, 5 and 6 of the instant antibody set forth in claim 1-(i) as evidenced by the sequence alignment shown below. Klein et al also teach that the antibody is humanized antibody with human sequences of frameworks FR1, FR2, FR3, and FR4 [0204, 0209-210]. Klein et al further teach the antigen binding fragments of the p95HER2 antibody comprising single chain Fv (scFv) [0202]
QY=Fuse SEQ ID NO: 1-2-3 (VH)
US-15-718-818-20 (US Patent: 10,882,918)
Sequence 20, US/15718818
Publication No. US20180118849A1
GENERAL INFORMATION
APPLICANT: Hoffmann-La Roche Inc.
TITLE OF INVENTION: BISPECIFIC T CELL ACTIVATING ANTIGEN BINDING MOLECULES
FILE REFERENCE: 51177-021001
CURRENT APPLICATION NUMBER: US/15/718,818
CURRENT FILING DATE: 2017-09-28
PRIOR APPLICATION NUMBER: EP 16191933.7
PRIOR FILING DATE: 2016-09-30
NUMBER OF SEQ ID NOS: 33
SEQ ID NO 20
LENGTH: 114
OTHER INFORMATION: p95HER2 VH
Query Match 83.8%; Score 127.4; Length 114;
Best Local Similarity 37.0%;
Matches 27; Conservative 0; Mismatches 0; Indels 46; Gaps 2;
Qy 1 DFGMS--------------TINTNGGTTHYPDNVKG------------------------ 22
||||| |||||||||||||||||
Db 31 DFGMSWIRQTPDKRLELVATINTNGGTTHYPDNVKGRFSISRDNAKKFVYLQMSSLKSDD 90
Qy 23 --------EGLDY 27
|||||
Db 91 TAIYYCPREGLDY 103
QY=Fuse SEQ ID NO: 4-5-6 (VL)
US-15-718-818-20 (US Patent: 10,882,918)
APPLICANT: Hoffmann-La Roche Inc.
TITLE OF INVENTION: BISPECIFIC T CELL ACTIVATING ANTIGEN BINDING MOLECULES
FILE REFERENCE: 51177-021001
CURRENT APPLICATION NUMBER: US/15/718,818
CURRENT FILING DATE: 2017-09-28
PRIOR APPLICATION NUMBER: EP 16191933.7
PRIOR FILING DATE: 2016-09-30
NUMBER OF SEQ ID NOS: 33
SEQ ID NO 21
LENGTH: 107
OTHER INFORMATION: p95HER2 VL
Query Match 81.1%; Score 106.3; Length 107;
Best Local Similarity 36.5%;
Matches 27; Conservative 0; Mismatches 0; Indels 47; Gaps 2;
Qy 1 KASQSVGTAVA---------------SASNRFT--------------------------- 18
||||||||||| |||||||
Db 24 KASQSVGTAVAWYQLKAGQSPKLLIYSASNRFTGVPDRFTGSGSGTDFTLTISNVQSEDL 83
Qy 19 -----QQYSTYPLA 27
|||||||||
Db 84 ADYFCQQYSTYPLA 97
Klein et al do not CAR or use this antibody to form a Chimeric Antigen Receptor (CAR).
Fan et al teach a Chimeric Antigen Receptor (CAR) having the structure as the figure shown below, which comprises single domain antibody scFv or an antigen binding fragment, CD28 as a transmembrane domain and as costimulatory domain and/or intracellular signaling domain, CD3zeta as one intracellular signaling domain, and CD8 as a hinge domain [0438]. Fan et al further teach nucleic acid encoding the CAR with leader sequence and teach expression vector and host cell comprising the nucleic acids, that are expressed in human T cell, specific CD8+ T cell ([0059, 0129, 0519-523] and examples).
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It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention was made to combine the teachings to form a CAR comprising the antigen binding fragment to p95HER2 with expected result. One of ordinary skill in the art before the effective filing date of was made would have been motivated with reasonable expectation of success to apply the teaching of Klein et al with the teachings of Fan et al in order to benefit immune therapy for a condition associated with abnormal p95HER2 because Klein et al have shown the antibody and antigen binding fragment scFv to p95HER2 and Fan et al have shown structures and materials of CARs as well as method of forming a CAR. Therefore, the references in combination teach every limitation of the claims and the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the invention was made, absent unexpected results.
Improper Markush grouping
Claim 1, 3 and 31 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 706.03(y).
The Markush grouping of antibodies set forth in the claims is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
each of the antibodies has unique CDRs and VH/VL sequences which are not shared by the other antibody listed in the claims. The elected antibody comprising VHCDRs of SEQ ID Nos: 1, 2, and 3 paired to VLCDRs of SEQ ID Nos: 4, 5 and 6 or functional equivalent antibodies does not share and have common structure in sequences and binding epitopes with the other antibodies listed in the claims.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Lei Yao, whose telephone number is (571) 272-3112. The examiner can normally be reached on 8:00am-6:00pm Monday-Friday.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis, can be reached on (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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/LEI YAO/Primary Examiner, Art Unit 1642