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
Applicant's election with traverse of the species of:
A first pairing of HER2 inhibitor VH and VL: SEQ ID NOs: 87 and 91, respectively
A second pairing of HER2 inhibitor VH and VL: SEQ ID NOs: 88 and 91, respectively
CDRs for the anti-PDL1 single chain antibody: CDR 1, 2 and 3 = SEQ ID NOs: 3, 4 and 5, respectively (VH= SEQ ID NO: 6)
CDRs for the anti-CTLA4 single chain antibody: CDR 1, 2 and 3 = SEQ ID NOs: 17, 18 and 19, respectively (VH= SEQ ID NO: 20)
HER2 mutations: T862A and H878Y
in the reply filed on 4/27/2026 is acknowledged. The traversal is on the ground(s) that: Applicant argues MPEP 803 requires the showing of a burden on the search. Applicant contends that the claims of the present invention would be part of an overlapping search area. Applicant further notes electronic searching allows for a search of many, or theoretically all, subclasses without substantial additional effort.
This is not found persuasive because: In response, as stated in p. 4, ¶ 5 of the Requirement for Restriction of 2/27/2026, Applicant is claiming a total of 37,440 distinct combinations of distinct HER2 binding species, PDL1 binding species and CTLA4 binding species. While an it is possible to search many sequences at once electronically, each sequence search produces results from 8 databases that the examiner must review manually to search for potential matches (or next nearest prior art) that also meets the priority date of the instant application. This is a serious burden.
The requirement is still deemed proper and is therefore made FINAL.
Claims 1-20 are currently pending
Claims 6, 14, and 17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 02/27/2026
Claims 1-5, 7-13, 15-16 and 18-20 will be examined on the merits.
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 1-5, 7-13, and 18-20 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 1-13
Claim 1 recites a comma-delineated list of three “wherein” statements immediately following “administering to the subject a HER2 inhibitor”. There is no conjunction (“and”, “or”, etc…) between the penultimate and final “wherein” list element. This renders the metes and bounds of claim 1 unclear because it is not clear whether one needs to satisfy all of the “wherein” list element limitations to satisfy claim (the “and” case) or whether one need only satisfy one of the “wherein” list elements to satisfy claim 1 (the “or” case) and, as such, this renders the claim indefinite.
Note: for the purposes of examination claim 1 will be examined with respect to explicitly elected species limitations only and the claim will be interpreted to require all explicitly elected species limitations.
Claims 18-20
Claim 18 recites an eight-element, comma delineated list elements, each beginning with “wherein”. The list does not contain any conjunction between the penultimate and final list element and, as such, it is unclear if satisfying the claim requires satisfying only one “wherein” element (“or” case), or if it requires satisfying all of the “wherein” elements (the “and” case) or some combination thereof. As such, the metes and bounds of the claim are unclear and the claim is indefinite.
Note: for the purposes of examination claim 18 will be examined with respect to explicitly elected species limitations only and the claim will be interpreted to require all explicitly elected species limitations.
Claim Rejections - 35 USC § 103
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 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, 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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The factual inquiries 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.
Claim(s) 1-5, 7-10 and 18-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Xu (Xu, et al., US 20190031782A1; Published 1/31/2019) in view of Nagano (Nagano, et al., Clin. Canc. Res. 2018 24(20):5112) and Hubalek (Hubalek, et al., Breast cancer: Targets and Therapy 2012 4:65).
Xu teaches on the subject of bispecific antibodies comprising common light chains (Xu, Abstract). Xu teaches that due to their strong target specificity, monoclonal antibodies can only inhibit one target, while many diseases (including tumors), inhibiting multiple antigen sites/epitopes is beneficial and that bispecific antibodies recognizing two or more epitopes have been used to address this issue (Xu, ¶ 0002). Xu teaches that trastuzumab is a HER2 -targeting antibody known to be effective vs breast cancer (Xu, ¶ 0009) and that pertuzumab is another HER2-targeting antibody binding the extracellular domain H of HER2 and is also used as a treatment for breast cancer (Xu, ¶ 0009). Regarding the limitation recited in claims 2, 15 and 18 that the first heavy chain and first light chain and the second heavy chain and second light chain self-assemble under physiological conditions or in vitro, Xu teaches that the common light chain of the bispecific antibody of Xu is capable of assembling with a HC of pertuzumab and a HC of trastuzumab (Xu, ¶ 0019). Regarding the limitation recited in claims 2, 15 and 18 that the two heavy chains self-assemble to form a heterodimer under physiological conditions or in vitro, Xu teaches that the bispecific antibodies of Xu comprise a Fc fragment of a HC that is modified to facilitate homodimer formation (Xu, ¶ 0017).
Regarding the HER2 inhibitor structural limitations recited in claims 2, 15 and 18, Xu teaches that the common VL comprises amino acids 1-107 of Xu’s SEQ ID NO: 1 (this is a 100% match for instant SEQ ID NO: 91) (Xu, ¶ 0035) and the first VH of the bispecific anti-HER2 antibody of Xu comprises Xu’s SEQ ID NO: 23 (100% match for instant SEQ ID NO: 87; corresponding to trastuzumab) and the second VH of the bispecific anti-HER2 antibody of Xu comprises Xu’s SEQ ID NO: 24 (100% match for instant SEQ ID NO: 88; corresponding to pertuzumab) (Xu, ¶ 0038) (hereinafter “the bispecific anti-HER2 antibody of Xu”). Regarding dosage levels, Xu teaches that the anti-HER2 bispecific antibody of Xu is effective at doses ranging from 10-30 mg/kg (Xu, ¶ 0273; Fig. 27). Xu also teaches that when mice were dosed at 10 mg/kg of the bispecific anti-HER2 antibody of Xu that the bispecific antibody was metabolized significantly faster than trastuzumab (Xu, Fig. 21):
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Xu does not teach a method of treating HER2+ breast cancer with T862A/H878Y mutations comprising the steps of sequencing the patient’s HER2 gene using NGS, identifying the presence of T862A/H878Y mutations in the subject’s HER2 gene and then administering the patient the bispecific anti-HER2 antibody of Xu. Xu does not teach that the bispecific anti-HER2 antibody of Xu is administered at about 20 mg/kg once every two weeks.
Nagano teaches on the subject of the evaluation of HER2 mutants via NGS as well as the effect of such mutations on treatment efficacy (Nagano, Abstract). Nagano teaches that NGS techniques have identified several key mutations of HER2 amongst various cancers but the clinical significance of infrequent mutations has yet to be established (Nagano, Abstract). Nagano teaches that cells identified has having HER2 mutations were tested vs several targeted drugs, including trastuzumab (Nagano, p 5115, ¶ 3), with the mutation specific relative efficacy of trastuzumab being depicted in the Fig 2A of Nagano (Nagano, Fig. 2):
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(Note: “relative viability” is the ratio of cell growth in the presence of trastuzumab divided by cell growth in the presence of a DMSO control at the same concentration (Xu, Fig. 2)
Note that Fig. 2A of Nagano indicates that H878Y mutant HER2 is responsive to trastuzumab treatment but that T862A mutant HER2 is not responsive to trastuzumab treatment.
Hubalek teaches on the subject of pertuzumab in the treatment of HER2 positive breast cancer (Hubalek, Abstract). Hubalek teaches that trastuzumab and pertuzumab bind distinct epitopes on HER2 without competing with each other, resulting in distinctive mechanisms for disrupting HER2 signaling (Hubalek, Abstract). Hubalek teaches that pertuzumab binds to domain II of the extracellular domain of HER2 and works by inhibition of dimerization and trastuzumab works via binding to domain IV of the extracellular domain and works by direct antibody binding (Hubalek, Fig. 1):
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It would be prima facie obvious to one of ordinary skill in the art to combine the administration of the bispecific anti-HER2 antibody of Xu for HER2+ breast cancer taught by Xu with the NGS sequencing taught by Nagano and arrive at a method of treating HER2+ breast cancer with T862A/H878Y mutations comprising the steps of sequencing the patient’s HER2 gene using NGS, identifying the presence of T862A/H878Y mutations in the subject’s HER2 gene and then administering the patient the bispecific anti-HER2 antibody of Xu in view of the teachings of Nagano and Hubalek. One of ordinary skill in the art would be motivated to do this in order to better treat breast cancer. One of ordinary skill in the art would have a reasonable expectation of success to combining the administration of the bispecific anti-HER2 antibody of Xu for HER2+ breast cancer taught by Xu with the NGS sequencing taught by Nagano and arriving at a method of treating HER2+ breast cancer with T862A/H878Y mutations comprising the steps of sequencing the patient’s HER2 gene using NGS, identifying the presence of T862A/H878Y mutations in the subject’s HER2 gene and then administering the patient the bispecific anti-HER2 antibody of Xu in view of the teachings of Nagano and Hubalek because: 1) Xu teaches a bispecific anti-HER2 antibody with one arm of the antibody being from trastuzumab and the other being from pertuzumab that is administered in methods of treating HER2 expressing breast cancer, 2) Nagano teaches that NGS of HER2 can reveal the presence of mutations that can impact treatment efficacy, with Nagano teaching that H878Y mutant HER2 is susceptible to trastuzumab-based therapy while T862A mutant HER2 is not susceptible to trastuzumab, 3) Hubalek teaches that trastuzumab and pertuzumab bind distinct epitopes on different domains of the extracellular portion of HER2 and have independent mechanisms of action and 4) one of ordinary skill in the art would reasonably deduce that the pertuzumab arm of the bispecific anti-HER2 antibody of Xu would be able to bind to T862A mutated HER2 (and thus be able to act as an efficacious treatment) even though trastuzumab does not bind to this mutant because Hubalek teaches that teaches that trastuzumab and pertuzumab act via completely independent mechanisms, with the epitopes recognized by trastuzumab and pertuzumab being completely distinct from each other and are located on different domains of the extracellular domain of HER and one of ordinary skill in would reasonably deduce that the epitope of HER2 recognized by the pertuzumab arm of the bispecific anti-HER2 antibody of Xu would be unaffected to the changes in the epitope caused by T862A that affects the trastuzumab epitope on distinctness of the two epitopes coupled with the fact that the two epitopes are located on different extracellular domains coupled with the fact that the trastuzumab epitope and the pertuzumab epitope are distant from each other.
Note: regarding claim 7 specifically, one of ordinary skill in the art would expect a patient having T862A mutated HER2 to be resistant to trastuzumab monotherapy because Nagano teaches that T862A mutant HER2 is resistant to trastuzumab treatment.
It would be prima facie obvious to one ordinary skill in the art to administer the bispecific anti-HER2 antibody of Xu at 20 mg/kg every two weeks in view of the teachings of Xu and applying routine experimentation. One of ordinary skill in the art would be motivated to do this in order better treat breast cancer. Xu teaches effective doses of the bispecific anti-HER2 antibody of Xu between 10-30 mg/kg. Fig 21 of Xu also shows that the anti-HER2 bispecific antibody of Xu is nearly completely cleared from the subject’s system 600 hr after administration (same as 25 days). One of ordinary skill in the art would be motivated to engage in routine experimentation of the dosage and interval in order to balance efficacy vs deleterious side effects. One or ordinary skill in the art would have a reasonable expectation of success starting with the 10-30 mg/kg dosage range and 600 hr pharmacokinetic range taught by Xu and arrive at a dosage of 20 mg administered every two weeks via routine experimentation because routine experimentation is within the purview of one of skill in the art. Additionally, “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)
Claim(s) 1-5, 7-12, 15 and 18-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Xu (Xu, et al., US 20190031782A1; Published 1/31/2019) and Nagano (Nagano, et al., Clin. Canc. Res. 2018 24(20):5112) and Hubalek (Hubalek, et al., Breast cancer: Targets and Therapy 2012 4:65) as applied to claims 1-5, 7-10 and 18-20 above and in further view of Choi (Choi, et al., EMBO Reports 2019 20: e48058).
The combined teachings of Xu, Nagano and Hubalek are discussed above.
The combined teachings of Xu, Nagano and Hubalek does not teach the combined method of Xu, Nagano and Hubalek further comprising administration of dinaciclib.
Choi teaches on the subject of CDK12 and its effects on trastuzumab resistance in breast cancer (Choi, Abstract). Choi teaches that CDK12 kinase inhibition facilitates anticancer efficacy of trastuzumab in HER2+ tumors and mice bearing trastuzumab-resistant HER2+ tumors are sensitive to CDK12 inhibition (Choi, Abstract). Choi teaches that one such CDK12 inhibitor used to treat breast cancer is dinaciclib (Choi, p2, ¶ 4).
It would be prima facie obvious to one of ordinary skill in the art to combine the method
It would be prima facie obvious to combine the method collectively taught by Xu, Nagano and Hubalek, said a method comprising the steps of sequencing the patient’s HER2 gene using NGS, identifying the presence of T862A/H878Y mutations in the subject’s HER2 gene and then administering the patient the bispecific anti-HER2 antibody of Xu with the dinaciclib of Choi to arrive at a method of treating HER2+ breast cancer with T862A/H878Y mutations comprising the steps of sequencing the patient’s HER2 gene using NGS, identifying the presence of T862A/H878Y mutations in the subject’s HER2 gene and then administering the patient the bispecific anti-HER2 antibody of Xu and the dinaciclib of Choi. One of ordinary skill in the art would be motivated to do this in order to better treat breast cancer. One of ordinary skill in the art would have a reasonable expectation of success making this combination because Choi teaches that trastuzumab-resistant tumors are sensitive to CHK12 inhibitors like dinaciclib and Hubalek teaches that T862A tumors are trastuzumab-resistant.
Claim(s) 1-5, 7-13, 15-16 and 18-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Xu (Xu, et al., US 20190031782A1; Published 1/31/2019) and Nagano (Nagano, et al., Clin. Canc. Res. 2018 24(20):5112), Hubalek (Hubalek, et al., Breast cancer: Targets and Therapy 2012 4:65) and Choi (Choi, et al., EMBO Reports 2019 20: e48058) as applied to claims 1-5, 7-12, 15 and 18-20 above and in further view of Xu (Xu, et al., WO 2019233413; Published 12/12/2019).
The combined teachings of Xu, Nagano, Hubalek and Choi are discussed above.
The combined teachings of Xu, Nagano, Hubalek and Choi do not teach the method of treating breast cancer collectively taught by Xu, Nagano, Hubalek and Choi discussed above further comprising a PDL1/CTLA bispecific dimer comprising a PDL1-recognizing single domain antibody comprising HC CDRs 1, 2 and 3 of SEQ ID NOs : 3, 4 and 5, respectively linked to a first Fc domain and a CTLA4 recognizing single domain antibody comprising HC CDRs 1, 2 and 3 of SEQ ID NOs: 17, 18 and 19, respectively, linked to a second Fc domain, wherein the first and second Fc domains form a dimer.
Xu teaches on the subject of a dimer formed by two polypeptide chains, each comprising an antibody Fc unit and two or more immunoglobin single variable domains (ISVDs) with one ISVD specific for CTLA4 and the other specific for PDL1 (Xu, Abstract). Xu teaches that the PDL1/CTLA4 bispecific Fc dimer of Xu comprises a PDL1-targeting ISVD comprising Xu’s SEQ ID NO:6 (100% match for all of instant claimed anti-PDL1 CDRs) (Xu claim 26) and a CTLA4-targeting ISVD comprising Xu’s SEQ ID NO: 20 (100% match for all instant claimed anti-CTLA-4 CDRs) (Xu, claim 20). Xu also teaches that the PDL1/CTLA4 bispecific Fc dimer of Xu is administered in methods of treating breast cancer (Xu, ¶ 00212).
It would be prima facie obvious to one of ordinary skill in the art to combine the method of treating breast cancer collectively taught by Xu, Nagano, Hubalek and Choi with the administration of the PDL1/CTLA4 bispecific Fc dimer for breast cancer taught by Xu (2019). The net result of this modification would be the method of treating breast cancer collectively taught by Xu, Nagano, Hubalek and Choi described in the previous rejection, further comprising administration of the PDL1/CTLA4 bispecific Fc dimer of Xu. One of ordinary skill in the art would have a reasonable expectation of success making this combination because combining two compositions each of which are taught in the prior art to be useful for the same purpose in order to form a third composition also for that purpose is a prima facie obvious combination (see MPEP 2144.06). In the instant case Xu, Nagano and Hubalek collectively teach the bispecific anti-HER2 antibody of Xu for treating breast cancer, Choi teaches dinaciclib for treating breast cancer and Xu (2019) teaches the PDL1/CTLA4 bispecific Fc dimer of Xu (2019) as a treatment for breast cancer. Hence, all components are taught in the prior art for the same purpose and, as such, combining them for that same purpose is a prima facie obvious combination.
Conclusion
Claims 1-5, 7-13, 15-16 and 18-20 are rejected.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Sydney Van Druff whose telephone number is (571)272-2085. The examiner can normally be reached 10 am - 6 pm.
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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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/SYDNEY VAN DRUFF/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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