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 .
Claim Status
Applicant’s preliminary amendments received 08MAY2023 are acknowledged.
Claims 5, 7-10, 12, and 14 have been canceled.
Claims 3-4, 6, 11, 13, 15-16, 18, and 20-24 have been amended.
Claims 25-27 are new.
Claims 1-4, 6, 11, 13, and 15-27 are pending in the instant application.
Priority
The present application is a 371 National Stage of PCT International Application No. PCT/CN2021/088674, filed 21APR2021, which claims foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy of CN 202010324761.8 filed on 22SPR2020 has been received and is acknowledged.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on 29NOV2022 is/are acknowledged and the references cited therein have been considered.
Specification
The disclosure is objected to because of the following informalities:
CROSS-REFERENCE TO RELATED APPLICATIONS section should be updated to reflect that this application is a 371 National Stage of PCT International Application No. PCT/CN2021/088674, filed 21APR2021.
“Corning Jerry Company” disclosed on p 3, should be updated to “Suzhou Alphamab Co., Ltd.” as a way to maintain consistency and accuracy of the applicants involved in the development of KN035. See US patent: US 11225522 B2.
Appropriate correction is required.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (p 12, lines 9 and 14). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
Claim 15 is objected to because of the following informalities:
Claim 15 is presumed to be missing “conjugate” between “antibody-drug” and “, comprising.” 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.
Claims 4, 6, 11, 13, 20, 23-24, and 27 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.
Claims 4, 6, 11, 13, 23-24, and 27, recite the phrase "optionally," which renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(h)(II). Claim 20 is also rejected since it depends from claim 11, but does not remedy this deficiency.
Enablement
Claims 1-4, 6, 11, 13, and 15-27 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Scope of the claim:
In the instance of claim 1, the claimed invention is drawn to an anti-PDL1 sdAb characterized by the CDRs 1-3 as shown in SEQ ID NOs: 43-45, respectively, and as written in not fully enabled due the language “characterized by” and “as shown in” which encompasses mutations within the sequences. However, “An anti-PDL1 sdAb comprising CDRs 1-3 of the VHH, consisting of SEQ ID NOs: 43-45, respectively” is enabled. Dependent claims are also rejected since they depend from claim 1, but do not remedy this deficiency.
Regarding claims 6, 11, 13, 20, and 23, the nature of the invention is drawn to methods for preventing or treating an abnormal proliferative disease comprising the step of administering a therapeutically effective amount of the anti-PDL1 sdAb of claim 1, a humanized anti-PDL1 sdAb of claim 6, or a composition of the humanized anti-PDL1 sdAb of claim 11 to a subject in need. These claims are not fully enabled because there is no guidance in the working examples indicating that the sdAb alone (i.e., VHH only, not humanized or humanized) prevents or treats abnormal proliferative disease and while the sdAb fusion protein hzF2 is therapeutically effective, there is no evidence that it is prophylactically effective against a murine colon cancer model. Additionally, the prior art supports utilizing anti-PDL1 VHH in the treatment of cancer for example; however, there is no support for anti-PDL1 as a prophylactic.
The nature of the invention of claims 15 and 26 is a multispecific sdAb or a targeted antibody-drug [conjugate], comprising the sdAb and methods of preventing or treating abnormal proliferative diseases comprising the step of administering multispecific/ADC sdAb. In this instance, claims 15 and 26 are not fully enabled because of the breadth of the multispecific/ADC sdAb structures, the lack of guidance in the specification, the lack of working examples supporting how to make multispecific or ADC sdAb as well as how to use the multispecific or ADC sdAb, and the lack of predictability in the prior art.
Claims 21-22, 24, and 27 are drawn to methods of diagnosing and evaluating the development and progress of an abnormal proliferative disease or predicting or evaluating the therapeutic effect of a PD1/PDL1 antagonist in a subject suffering from an abnormal proliferative disease by contacting the anti-PDL1 sdAb to a sample or using the anti-PDL1 sdAb to detect PDL1 expression. These claims are not fully enabled because there are no additional steps within the claim to reach the outcome of the claim and furthermore there are no working examples, wherein the expression of PDL1 was detected for diagnoses or therapeutic effect by contacting the anti-PDL1 sdAb, hzF2 with a sample.
Direction provided by the inventor and existence of working examples:
The specification discloses the preparation of antibody-based drugs which target human PDL1 and methods of use particularly as related to treatment and/or prevention, or diagnosis of PDL1 related diseases (p 1, technical field section). Working examples 1-10 of the specification disclose, the construction/screening/identification of VHH-F2 (i.e., SEQ ID NO: 1); characterization (i.e., binding activity, binding specificity) of the fusion protein VHH-F2-human Fc (i.e., chF2, SEQ ID NO: 3); humanization of the framework regions of chF2 (i.e., hzF2, VHH consisting of SEQ ID NO: 7, full-length sequence consisting of SEQ ID NO: 9); and in vitro inhibitory efficacy, half-life characterization in mice, and therapeutic efficacy of hzF2 sdAb fusion protein compared to known anti-PDL1 sdAb fusion protein, KN035 (i.e., SEQ ID NO: 5). Although, these examples support the specific monospecific hzF2 sdAb fusion protein comprising HCDRs 1-3 consisting of SEQ ID NOs: 43-45, respectively and a human Fc region and their therapeutic efficacy in mouse models wherein the hzF2 sdAb fusion protein performs negligibly better than KN035, it is unclear whether the same binding/inhibitory effect could be observed when incorporated into a multispecific antibody, whether the monospecific hzF2 sdAb fusion protein would be able to prevent an abnormal proliferative disease, whether the sdAb can detect PDL1 in tissue samples, or what steps are necessary for diagnosing/evaluating an abnormal proliferative disease or predicting/evaluating therapeutic efficacy of a PD1/PDL1 antagonist. Therefore, there is no guidance provided regarding making the bispecific antibodies, using the bispecific antibodies for prevention or therapy; using the monospecific sdAb antibodies for therapy, prevention, diagnosis, or determining therapeutic efficacy; or using the monospecific sdAb fusion proteins for prevention, diagnosis, or determining therapeutic efficacy.
State of prior art and level of predictability in the art:
Furthermore, the literature teaches the difference between prevention and therapy as well as the breadth of structures/predictability of the structures for making and using multispecific sdAb fusion proteins. In the instance of prevention vs therapy, the literature teaches that treatment provides increased control over a disease in patients that already have the disease (i.e., an abnormal proliferative disease such as cancer), prevention reduces the probability of a disease-free patient from getting the disease, and that while anti-PDL1 sdAb have shown clinical promise to treat cancer, evidence for prevention of the disease is not discussed. Specifically, it is well known in the art, that cancer treatment refers to the use of interventions (e.g., chemotherapy, radiation therapy, surgery, immunotherapy, or a combination thereof) to eliminate or control cancer cells that are already present in the body; whereas cancer prevention is an action taken (e.g., changes in diet and lifestyle, screening, chemoprevention) to lower the chance of getting cancer (see entire documents: NIH-NCI, Cancer Prevention Overview, 2023; Mayo Clinic, Cancer Treatment, 2024; and NCFR ,Cancer Intervention vs Prevention: What does it Mean?, 2024). The prior art teaches the use of anti-PDL1 sdAb and their bispecific versions for the treatment of an abnormal proliferative disease, such as cancer; however, the prior art does not teach anti-PDL1 sdAb and their bispecific versions for cancer prevention (Xi, et al., Biochim et Biophys Acta, 2025, 1880, 1-13, see section 2).
With regards to bispecific sdAb fusion proteins, there are a variety of formats including bivalent dAb/VHH, trivalent dAb/VHH, tetravalent dAb/VHH, VHH2-CH1/CL, Fab-VHH, IgG-[H]-VHH, or IgG-[L]-VHH, with each of them having their pros and cons (Brinkmann, et al., MABS, 2017, 9, 182-212, see Fig 2 and Zhong, et al., Sci Rep, 2022, 12, 1-11, see Fig 1). In the instance of IgG-[H]-VHH, or IgG-[L]-VHH, Zhong, et al., teach that placement of the VHH on the light chains weakened the IgG HC/LC pairing, placement of the VHH at the C-terminus of the HC reduced cytotoxicity of the parental VHH, and placement of the VHH at the N-terminus of the HC maintained the cytotoxicity of the parental VHH (Introduction section). Therefore, the literature supports that there are a wide variety of bispecific sdAb formats and the orientation of the VHH in the overall structure impacts the efficacy.
Quantity of experimentation needed to make or use the invention based on the disclosure:
Thus, one skilled in the art would be unable to make the anti-PDL1 bispecific/ADC sdAb and/or use the anti-PDL1 monospecific/bispecific/ADC sdAb as currently claimed. Therefore, the implementation of the invention in view of the breadth of variables (i.e., bispecific/ADC sdAb formats), level of predictability in the art, and the lack of direction provided by the specification and/or working examples, would require undue experimentation for one of ordinary skill in the art to make and/or use the instantly claimed invention.
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 1-4, 6, 11, 13, 15-20, 23, and 25-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of co-pending Application No. 18/006571; herein referred to as the “reference application.” Although the claims at issue are not identical, they are not patentably distinct from each other because the anti-TGFß RIII conjugate molecule characterized by an anti-human PDL1 nanobody (i.e., sdAb) set forth in SEQ ID NO: 20 and methods of making/use thereof of the reference application anticipates the anti-PDL1 sdAb (i.e., nanobody) characterized by CDRs 1-3 set forth in SEQ ID NOs: 43-45, respectively and methods of making/use thereof of the instant application. Specifically, the sequences of the anti-PDL1 nanobody as a part of an anti-TGFß RII conjugate molecule, methods of making, and methods of using of the reference application anticipates the CDRs of the anti-PDL1 sdAb as set forth in SEQ ID NO: 43-45 as well as the full-length humanized anti-PDL1 fusion antibody (i.e., hzF2-Fc, SEQ ID NO: 9) of the instant application, the bispecific sdAb, methods of making, and methods of using.
The co-pending claims of the reference application recite: A TGFßRII mutant, characterized by mutations as compared to SEQ ID NO: 6 (i.e., claim 1). An anti-TGFß RII conjugate molecule, characterized in that the antibody targets a target for tumor therapy and the anti-TGFß RII mutant has the amino acid sequence according to claim 1 (i.e., claim 13). The anti-TGFß RII conjugate molecule of claim 13, characterized in that the antibody is an anti-human PDL1 nanobody, wherein the amino acid sequence is set forth in SEQ ID NO: 20 (i.e., claim 17); A composition comprising the TGFßRII mutant of claim 1,…or a conjugate molecule of the TGFßRII mutant and a pharmaceutically acceptable excipient (i.e., claim 19). A nucleic acid encoding the TGFßRII mutant of claim 1,…or a conjugate molecule of the TGFßRII mutant (i.e., claim 20); a recombinant vector or recombinant host cell comprising the nucleic acid according to claim 20 (i.e., claim 21); A method for producing a product, characterized in that the method includes producing a TGFßRII mutant,…or a conjugate molecule thereof using the nucleic acid according to claim 20, or a recombinant vector or recombinant host cell comprising the nucleic acid (i.e., claim 22). A method of treating a disease, characterized in that the method comprises administering to a subject in need an effective amount of a product selected from the group consisting of TGFßRII mutant of claim 1,…a conjugate molecule of the TGFßRII mutant, a composition,… or a recombinant vector or recombinant host cell of the TGFßRII mutant (i.e., claim 25). The method according to claim 25, characterized in that the method is for preventing or treating cancer (i.e., an abnormal proliferative disease), selected from …non-small cell lung carcinoma… (i.e., claims 26-27).
In this instance, because anti-PDL1 nanobody of SEQ ID NO: 20 of the reference application comprises 93.4 % query match to CDR 1 (i.e., SEQ ID NO: 43, 1 amino acid difference), and 100% query match to CDRs 2 and 3 (i.e., SEQ ID NOs: 44 and 45, respectively) of the instant application, and because the language (i.e., “characterized by” and “shown in”) of claim 1 of the instant application encompasses mutations within the CDRs, the anti-PDL1 nanobody anticipates the anti-PDL1 sdAb (see OA.APPENDIX). Furthermore, because SEQ ID NO: 20 of the reference application has 99.1% query match to SEQ ID NO: 9 (i.e., claim 6) of the instant application and both bind PDL1, there is no clear difference in the scope between the products of the instant and reference applications. In response, it is suggested that applicant either file a terminal disclaimer or amend the claims such that a clear and unmistakable line of separation exists between the products and methods claimed in the instant application and those of the reference application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAMANTHA L. HOPKINS whose telephone number is (703)756-4666. The examiner can normally be reached Mon-Thurs 6:00 AM to 4:00 PM EST.
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/SAMANTHA LAKE HOPKINS/Examiner, Art Unit 1641
/MICHAEL SZPERKA/Primary Examiner, Art Unit 1641