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
Applicant’s election without traverse of a specific combination of CDRH1-3 of SEQ ID NOs: 3, 4, and 264, respectively, and CDRL1-3 of SEQ ID NOs: 6, 7, and 8, respectively in the reply filed on May 26, 2026 is acknowledged.
Claims 1, 6, 17-19, 26, 28, 34, and 35 have been amended.
Claim 39 has been added.
Claims 7-16, 23-25, 36, and 38 were previously cancelled.
Claims 1-6, 17-22, 26-35, 37 and 39 are pending and under consideration.
It is noted that prior art does not teach or suggest an anti-CD44 antibody comprising the elected CDR combination. The search is extended to other species encompassed by the claims and have the antigen-binding activity to CD44v6 (see Tables 12 and 13).
Priority
It is acknowledged that this application is a 371 of Internation Application No. PCT/US2022/018863 filed March 4, 2022, which claims the benefit of priority to U.S. Provisional Patent Appl. No. 63/157,601 filed March 5, 2021, U.S. Provisional Patent Appl. No. 63/223,698 filed July 20, 2021, and U.S. Provisional Patent Appl. No. 63/270,641 filed October 22, 2021. The priority date has been established as March 5, 2021.
Information Disclosure Statement
The Information Disclosure Statements filed on 04/26/2024, 04/25/2025 and 05/26/2026 have been considered and entered by examiner.
Claim Objections
Claim 1 objected to because of the following informalities: “2755and” should be “and”. Appropriate correction is required.
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 6 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.
The term “specifically binds” in “specifically binds to COSMC knock-out HaCaT cells” or “specifically binds to COSMC knock-out HEK293 cells recombinantly expressing CD44” of claim 6 is a relative term which renders the claim indefinite. The term “specifically binds” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. For example, if an antibody binds both “COSMC knock-out HaCaT cells” and “COSMC knock-out HEK293 cells recombinantly expressing CD44”, it is unclear whether the antibody can be considered as “specifically binds” to these cells or not.
Claim Rejections - 35 USC § 112
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.
Claims 4, 6, 17-22, 26-35, and 37 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.
Claim 4 is directed to an antibody or antigen-binding fragment which is humanized and comprises:
(a) a VH having a first sequence at least 95% identical to: (i) the VH designated as HV1-18A (SEQ ID NO:263), HV1-18B (SEQ ID NO:265), HV1-18C (SEQ ID NO:266) or HV1-18 Consensus (SEQ ID NO:265); (ii) the VH designated as HV1-46A (SEQ ID NO:267), HV1-46B (SEQ ID NO:269), HV1-46C (SEQ ID NO:270) or HV1-46 Consensus (SEQ ID NO:269); (iii) the VH designated as HV1-69A (SEQ ID NO:271), HV1-69B (SEQ ID NO:272), HV1-69C (SEQ ID NO:274) or HV1-69 Consensus (SEQ ID NO:272); or (iv) the VH designated as HV7-4-1A (SEQ ID NO:271), HV7-4-1B (SEQ ID NO:272), HV7-4-1C (SEQ ID NO:274) or HV7-4-1 Consensus (SEQ ID NO:276);
and (b) a VL having a second sequence at least 95% identical to: (i) the VL designated as LV7-43A (SEQ ID NO:277), LV7-43B (SEQ ID NO:278), LV7-43C (SEQ ID NO:279) or LV7-43 Consensus (SEQ ID NO:278); (ii) the VL designated as LV7-46A (SEQ ID NO:281), LV7-46B (SEQ ID NO:282), LV7-436 (SEQ ID NO:283) or LV7-46 Consensus (SEQ ID NO:282); or (iii) the VL designated as LV8-61A (SEQ ID NO:285), LV8-61 B (SEQ ID NO:286), LV8-61C (SEQ ID NO:287) or LV8-61 Consensus (SEQ ID NO:286), wherein the humanized antibody or antigen-binding fragment is a humanized antibody or antigen fragment.
By reciting “at least 95% identical to…”, up to 5 residues of each recited VH or VL can be varied (including insertion, deletion or substitution). These variations can occur at any location (> 100 positions) of a VH or VL (including CDR regions). Thus, the claim encompasses billions more possible variants for each recited SEQ ID NO. Furthermore, given Broadest Reasonable Interpretation (BRI), the claim encompass all possible combinations of any HV of option (a) and any LV of option (b), which would generate an even larger number of humanized antibodies or antigen binding fragments. The specification disclose only 8 humanized antibodies which binds to CD44 (Example 4, Tables 12 and 13).
The specification does not disclose other antibodies with other CDR variants, or CDR variant combinations encompassed by the claims with claimed properties, e.g. binding to CD44v6 (see claim 6). Thus, these claims lack written description because the specification lacks a representative number of species that satisfies the entirety of the genus.
Vas-Gath, Inc. v" Mahurkar, 19 USPQ2d 1111, makes clear that "to satisfy the written description requirement, an 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, and that the invention, in that context, is whatever is now claimed".
On 22 February 2018, the USPTO provided a Memorandum clarifying the Written Description Guidelines for claims drawn to antibodies, which can be found at www.uspto.gov/sites/default/files/documents/amgen_22feb2018.pdf. That Memorandum indicates that, in compliance with recent legal decisions, the disclosure of a fully characterized antigen no longer is sufficient written description of an antibody to that antigen. Accordingly, the instant claims have been evaluated in view of that guidance.
By the time the invention was made, it is well established in the art that the formation of an intact antigen-binding site in an antibody usually required the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three "complementarity determining regions" ("CDRs") which provide the majority of the contact residues for the binding of the antibody to its target epitope. Even a single point mutation in HCDR1 region could lead to antibody lose its binding activity (Ni et al., The Protein Journal, 43, pp. 683-696, July 2024, see Abstract). Thus, the specific antibody disclosed by the specification (e.g. 19L04) would not tell structure of other antibodies with CDR variants encompassed by rejected claims. Wong (Wong et al., MABS, 2021, Vol. 13, No. 1, e1873478, Publication Year: 2021) teaches that sequence-distant antibodies can target the same epitope (Abstract).
In view of above, the specification teaches 8 humanized anti-CD44 antibodies which bind to CD44v6, are summarized in the table below (based on Tables 4A-4G, 12, and 13):
Antibody
HCDRs: 1-3
VH
LCDRs: 1-3
VL
HV1-18A + LV7-43-A
SEQ ID NOs:3-4-264
SEQ ID NO: 263
SEQ ID NOs:6-7-8
SEQ ID NO: 277
HV1-46A + LV7-43-A
SEQ ID NOs:3-4-268
SEQ ID NO: 267
SEQ ID NOs:6-7-8
SEQ ID NO: 277
HV1-69A + LV7-43-A
SEQ ID NOs:3-4-268
SEQ ID NO: 271
SEQ ID NOs:6-7-8
SEQ ID NO: 277
HV1-7-4A + LV7-43-A
SEQ ID NOs:3-275-5
SEQ ID NO: 271
SEQ ID NOs:6-7-8
SEQ ID NO: 277
HV1-18A + LV7-46-A
SEQ ID NOs:3-4-264
SEQ ID NO: 263
SEQ ID NOs:6-7-8
SEQ ID NO: 281
HV1-46A + LV7-46-A
SEQ ID NOs:3-4-268
SEQ ID NO: 267
SEQ ID NOs:6-7-8
SEQ ID NO: 281
HV1-69A + LV7-46-A
SEQ ID NOs:3-4-268
SEQ ID NO: 271
SEQ ID NOs:6-7-8
SEQ ID NO: 281
HV1-7-4A + LV7-46-A
SEQ ID NOs:3-275-5
SEQ ID NO: 271
SEQ ID NOs:6-7-8
SEQ ID NO: 281
It is noted that SEQ ID NO: 275 comprises SEQ ID NO: 4; SEQ ID NO: 5 comprises SEQ ID NO: 268; and SEQ ID NO: 268 comprises SEQ ID NO: 264. Thus, all these antibodies comprise HCDRs: 1-3 of SEQ ID NOs: 3-4-264 and LCDRs: 1-3 of SEQ ID NOs: 6-7-8. The specification does not disclose any antibodies which bind to CD44v6 with a CDR combination different from the disclosed antibodies. Thus, one ordinary skill in the art would not be able to visualize other humanized antibody encompassed by the claim which would have the same properties as the ones disclosed in the table above.
In addition, the claims identify the humanized antibodies by function only, where the function is to:
binds to a CD44v6 glycopeptide GYRQTPKEDSHSTTGTAAA (SEQ ID NO:165) that has been glycosylated with GaINAc on threonine at amino acid position 5 of SEQ ID NO:165 and serine at amino acid position 12 of SEQ ID NO:165 (claim 6);
specifically binds to COSMC knock-out HaCaT cells (claim 6);
specifically binds to COSMC knock-out HEK293 cells recombinantly expressing CD44 (claim 6);
treating cancers (claim 35), which would encompass all possible cancers.
The specification and prior art have not established the relationship between the claimed functions and the structure of the antibody. One of ordinary skilled in the art would not be able to readily recognize/visualize a humanized antibody with required properties. Cancers are not a single diseases, different cancers may have different origins and different clinical responses. In fact, there is no any antibody can be used to treat all cancers. Taken together, applicant has not provided sufficient evidence to show that the inventors possess a genus of humanized antibodies or antigen-binding fragments as claimed.
Claim 5 recites specific pair of VH and VL. However, the claim also encompasses a large number of variants by reciting “at least 95% identical to”. As set forth above, the specification does not provide sufficient written description support for these variants.
Claims 6, 17-22, 26-30, and 34 also encompass the humanized antibody or antigen-binding fragments of claim 1, thus, these claims lack written description support as set forth above.
In addition, claims 19-22 recites additional antigen-binding moiety, including antibodies binding to “a T-cell epitope”. The claims do not limit the term “a T-cell epitope”. Given BRI, thus, the claims at least encompass all possible antibodies (known or unknown) to all possible T-cell epitopes (known or unknown). Other than general description of T cell epitopes (see [0812] of instant publication US 2025/0326855 A1), however, as set forth above, “the disclosure of a fully characterized antigen no longer is sufficient written description of an antibody to that antigen”. Thus, the specification lacks written description for antibodies binding to a second ecotype.
Regarding claims 31-33, 35, and 37, since the specification does not have the written description support for the antibody or antigen-binding fragment, logically, the specification would not have the support for nucleic acid encoding the antibody or antigen binding fragment, or method of using the antibody or antigen-binding fragment.
Therefore, for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-3 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 68-97 of copending Application No. 17/909,045 (hereinafter Appl. 045), in view of Safdari (Safdari et al., Biotechnology and Genetic Engineering Reviews, Vol. 29, No. 2, 175-186, Publication Date:08/02/2013).
The claims of Appl. 045 teach an anti-glyco-CD044 antibody or antigen-binding fragment, which has a VH comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO:1 and a VL comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO:2 (claims 68 and 69).
The claims of Appl. 045 teach a method of treating cancer comprising administering to a subject in need thereof an effective amount of the anti-glyco-CD44 antibody or antigen binding fragment (claim 89).
As show below, SEQ ID NO: 1 comprises a VH comprising HCDRs 1-3 of SEQ ID NOs: 3-4-264 of the instant application; and SEQ ID NO: 2 comprises a VL comprising LCDRs 1-3 of SEQ ID NOs: 6-7-8 of the instant application.
SEQ ID NO: 1 of Appl. 045 alignment:
US-17-909-045-1
Query Match 82.7%; Score 121.5; Length 118;
Best Local Similarity 31.2%;
Matches 25; Conservative 0; Mismatches 0; Indels 55; Gaps 2;
Qy 1 GYTFTSYW-----------------IYPRSGTT--------------------------- 16
|||||||| ||||||||
Db 26 GYTFTSYWMHWVKQRPGQGLEWIGNIYPRSGTTNYDGYFKSKATLTVDTSSSTAYMQLSS 85
Qy 17 -----------TRSGYDYPF 25
|||||||||
Db 86 LTSEDSAVYFCTRSGYDYPF 105
SEQ ID NO: 2 of Appl. 045 alignment:
Query Match 77.6%; Score 87.7; Length 109;
Best Local Similarity 28.4%;
Matches 21; Conservative 0; Mismatches 0; Indels 53; Gaps 2;
Qy 1 TGAVSIRNY-----------------GTN------------------------------- 12
||||||||| |||
Db 26 TGAVSIRNYANWVQEKPDHLFTGLIGGTNNRAPGVPARFSGSLIGDKAALTITGAQPEDE 85
Qy 13 -----ALLYSNYWV 21
|||||||||
Db 86 AIYFCALLYSNYWV 99
Thus, the antibody of Appl. 045 comprises the same CDRs as the antibody encompassed by the instant claims 1-3. However, the claims of Appl. 045 do not teach that the antibody is a humanized antibody.
Safdari teaches antibodies have emerged as effective tools in the treatment and diagnosis of different human diseases. Non-human antibodies have been demonstrated to induce human immune responses, which result in neutralization of administered antibody and limits the application of such antibodies in treatment of human diseases. To overcome this problem the technology of antibody humanization has been developed. Antibody humanization is an efficient approach to eliminate or reduce the immunogenicity of these antibodies (Introduction).
Safdari teaches different methods of making humanized antibodies (Table 1).
It would have prima facie been obvious to one of ordinarily skilled in the art before the time the invention was filed to make an anti-glyco-CD044 antibody or antigen-binding fragment, which has a VH of SEQ ID NO:1 and a VL of SEQ ID NO:2 for treating cancers as taught by the claims of Appl. 045, and to humanized the antibody as taught by Safdari. One of ordinary skill in the art would have had a reasonable expectation of success because 1) antibody humanization is an efficient approach to eliminate or reduce the immunogenicity of these antibodies; 2) the methods of making humanized antibody have been well-known in the field. The motivation would have been to generate an antibody with better therapeutic properties for treating human diseases.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Related Prior Art
Peng (Peng et al., Oncotarget, vol. 8, no. 49, 86747-86768, Publication Date: 10/17/2017, cited in IDS of 04/26/2024) teaches that bivatuzumab, a humanized mAb directed against CD44v6, showed some clinical success (the whole document, e.g. page 86478, col. 1, last paragraph). However, Peng does not teach any antibody with the CDR sequences as instantly claimed.
Da Cruz (da Cruz et al., US 2015/0374848 A1, Publication Date: 12/31/2015, cited in IDS of 04/26/2024) discloses humanized anti-CD44 antibody PTA-4621 (RO5429083) that target a glycosylated, conformation-dependent epitope of CD44 ([0141]). This antibody was shown to be effective in several CD44+ in vivo models, including those derived from human leukemia, This example demonstrates that humanized PTA-4621 (RO5429083) inhibits tumor growth of the human CAL 27 head and neck carcinoma in an established xenograft model ([0176], [0183], Example 5). However, Da Cruz does not teach any antibody with the CDR sequences as instantly claimed.
Conclusion
Claims 1-6, 17-22, 26-35, 37 are rejected.
Claim 39 is objected because they are dependent on the rejected claims directly or indirectly. However, claim 39 would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHENG LU whose telephone number is (571)272-0334. The examiner can normally be reached Monday-Friday 8-5.
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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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/CHENG LU/ Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/ Supervisory Patent Examiner, Art Unit 1642
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