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 .
Application Status
The amended claims filed with Response to the non-final Office Action on December 4, 2025 have been entered. Claims 1, 3-6, 8, 13-16, 18-20, and 22 are pending. Claims 2, 7, 9-12, 17, and 21 are canceled. Claims 1, 5-6, 13, and 18 are amended. Claim 20 remains withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 1, 3-6, 8, 13-16, 18-19, and 22 are under examination herein.
Objections to the Specification Withdrawn
All prior grounds of objection to the specification are withdrawn in view of Applicant's amendments.
Claim Objections Withdrawn
The objection to claim 18 is withdrawn in view of Applicant's amendments thereto.
Claim Rejections Withdrawn
All prior grounds of rejection over claims 2, 7, 17, and 21 are rendered moot in view of the cancelation of the claims.
The rejection of claim 5 under 35 U.S.C. § 112(b) is withdrawn in view of Applicant's claim amendments thereto.
The rejection of claims 1, 3-6, 8, 13-16, 18-19, and 21-22 under 35 U.S.C. § 112(a) for failing to comply with the written description requirement are withdrawn in view of Applicant's amendments to claims 1 and 13.
The rejection of claims 13-14 and 18-19 under 35 U.S.C. § 112(a) over scope of enablement is withdrawn in view of Applicant's amendments to claim 13.
NEW OBJECTIONS AND MAINTAINED REJECTIONS
Objection to the Specification (New)
The disclosure is objected to because of the following informalities: The amended description of Figure 2 (page 22) recites that data are shown for “the co-administration of Trastuzumab/Pertuzumab and the co-administration of/Trastuzumab”. Based on the content of Figure 2, it is believed that the latter should instead recite “of MAB270/Trastuzumab” for clarity. Appropriate correction is required.
Claim Objections (New)
Claim 6 is objected to because of the following informalities: The wherein clause of the claim recites “wherein the second HER2 inhibitor is an anti-HER2 antibody binding comprising trastuzumab or pertuzumab.” It is suggested that “binding” (underlined) be removed for clarity.
Appropriate correction is required.
Claim Rejections - 35 USC § 103 (Maintained)
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 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.
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.
(1)
Claims 1, 3-6, 8, 13-16, and 18-19 are rejected under 35 U.S.C. 103 as being unpatentable over Fischer (WO 2017/191327 A2; cited in IDS) in view of Lee (EP 2998319 A1; cited in IDS). This rejection has been updated to reflect Applicant’s claim amendments.
Fischer discloses antibodies or antigen-binding fragments thereof that specifically bind to HER2 at a different epitope than trastuzumab as well as pharmaceutical compositions comprising the same (page 3). In one embodiment, a humanized anti-HER2 antibody of the invention denoted “B100” comprises a VH comprising the amino acid sequence of SEQ ID NO: 4 (which shares 100% identity to the instantly claimed VH comprising SEQ ID NO: 80, with its corresponding CDRs and FRs) and a VL comprising the amino acid sequence of SEQ ID NO: 10 (which shares 100% identity to the instantly claimed VL comprising SEQ ID NO: 89, with its corresponding CDRs and FRs) (pages 14-16; Figures, pages 1-2), relevant to claims 1 and 3-5. See sequence alignments between Fischer (Qy) and the instant application (Db) below:
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Fischer teaches that the antibodies of the invention have favorable properties including increased induction of FcR-mediated signaling activity and the capability of inducing apoptosis with an efficacy similar to a cytotoxic drug like camptothecin (pages 19-22). Fischer teaches that the latter quality “will be additive to the activity of other HER2 antibodies with different modes of action” (page 22, lines 14-24).
Relevant to claims 13-14 and 18-19, Fischer further discloses a method of treating a HER2-mediated disease (e.g., breast cancer, pancreatic cancer, or colon cancer) in a patient which comprises administering a pharmaceutical composition comprising an antibody according to the invention to the patient (page 2, Summary of invention; page 26).
Fischer further teaches that there is a need for the development of novel, more effective antibodies that can be used in follow-up therapies when clinical results with trastuzumab and chemotherapy are unsatisfying or as an alternative in combination with existing antibodies such as trastuzumab (page 3, Background).
However, Fischer does not expressly teach a pharmaceutical composition comprising antibody B100 further in combination with a second HER2 inhibitor (e.g., trastuzumab), nor a method of treating a HER2-positive cancer by administering a pharmaceutical composition comprising such a combination.
Lee teaches that although trastuzumab is the most commercially successful anti-HER2 antibody, it only shows therapeutic efficacy in 15% of breast cancer patients overexpressing HER2 (¶ 0006-0007). Accordingly, efforts have centered on improving the prognosis of non-responsive or poorly responsive HER2-positive cancer patients by combination therapy, e.g., with the anti-HER2 antibodies trastuzumab and pertuzumab (¶ 0007-0009), relevant to claims 15-16. Lee discloses anti-HER2 antibodies and pharmaceutical compositions comprising the same which specifically bind to HER2 at an epitope different from trastuzumab, and which are administered in combination with trastuzumab to overcome limitations associated with trastuzumab monotherapy (Abstract; ¶ 0011-0017, 0081-0087), relevant to claim 6. Lee shows that the combination of the humanized antibody of the invention “hz1E11” and trastuzumab more strongly inhibits the proliferation of the NCI-N87 and OE-19 cancer cell lines when compared to monotherapy with trastuzumab or hz1E11 (Figure 8) and dose-dependently decreases tumor cell growth in an NCI-N87 xenograft animal model to a greater extent than trastuzumab monotherapy (Figure 9). The hz1E11 antibody, alone and in combination with trastuzumab, also more potently induces apoptosis of cancer cells than trastuzumab monotherapy (Figure 5).
Lee further discloses a kit comprising an anti-HER2 antibody of the invention (e.g., ¶ 0093-0097).
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to make and use a pharmaceutical composition comprising the combination of trastuzumab and a second anti-HER2 antibody, e.g., the B100 antibody taught by Fischer, in a method of treating a HER2-positive cancer, based on the collective teachings of Fischer and Lee. The skilled artisan would have been motivated to do so because, as taught by Lee, many patients with HER2-positive cancer do not respond to trastuzumab monotherapy, and a combinatorial treatment comprising two anti-HER2 antibodies that each bind a separate epitope of HER2 is more effective than either antibody alone. There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized that the anti-HER2 antibodies taught by Fischer (B100) and Lee (hz1E11) are functional equivalents in that both possess the same qualities of (1) binding specifically to HER2 at a different epitope than trastuzumab, and (2) potently inducing apoptosis of cancer cells. Accordingly, it would have been obvious to try substituting hz1E11 with B100 in a HER2 combination therapy.
Response to Arguments
Applicant's arguments filed December 4, 2025 have been fully considered but they are not persuasive.
Applicant traverses the rejection on the basis that neither Fisher nor Lee, alone or in combination, teach or suggest the combination of the B100 antibody (as the first anti-HER2 antibody used in the present application) and an anti-HER2 antibody that binds to a different subdomain of HER2 (Remarks at pages 12-13). Applicant states that Lee differs from the instantly claimed invention in that the two disclosed antibodies both bind to subdomain IV of the extracellular domain of the HER2 protein (Remarks at page 13). Applicant further submits that the combination of an antibody with the CDRs of B100 with trastuzumab or pertuzumab, which bind to different subdomains of HER2, display surprisingly synergistic effects as illustrated in Figures 2 and 3 (Remarks at pages 13-14). Applicant states that binding of trastuzumab and pertuzumab to HER2 are not blocked by antibody B100 and that the teachings of Lee provide no expectation of the synergistic effect of the combination of two inhibitors that bind different HER2 domains (Remarks at pages 13-14).
In response to Applicant's arguments regarding differences between the teachings of Lee and the instantly claimed invention, it is noted that the features upon which applicant relies (i.e., “a combination of antibodies that bind different domains”) is not required by the rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). In the present case, only claim 6 as amended recites that the instantly claimed pharmaceutical composition comprises as the second “HER2 inhibitor” an antibody, said antibody comprising trastuzumab or pertuzumab. Instead, the instant claims are more broadly drawn to a pharmaceutical composition comprising the combination of (1) an anti-HER2 monoclonal antibody comprising a combination of heavy chain and light chain CDRs as set forth in claims 1 and 13, and (2) a generic HER2 inhibitor. It is not required by the instant claims (except for claim 6) that the HER2 inhibitor possesses the additional function of binding to HER2. Thus, the HER2 inhibitor is not limited to antibodies, let alone antibodies that bind to a separate epitope of HER2 than the first reagent in the composition. For example, the HER2 inhibitor could be a tyrosine kinase inhibitor such as lapatinib or tucatinib.
In response to Applicant's arguments regarding surprising results, it is acknowledged that Figures 2-3 appear to show an effect of the combination of the antibody MAB270 (which comprises the heavy chain CDRs comprising the amino acid sequences of SEQ ID NO: 1-3, respectively, and the light chain CDRs comprising the amino acid sequences of SEQ ID NO: 4, 5, and 7, respectively) with trastuzumab on mean tumor volume over time (in particular, after more than about 40 days following tumor transplantation) and individual tumor volume at day 62. However, it is first noted that antibody B100 (as elected by Applicant pursuant to the election of species requirement mailed on February 20, 2025) comprises light chain CDRs comprising the amino acid sequences of SEQ ID NO: 4-6, respectively (i.e., differing in the LCDR3 structure). Secondly, despite Applicant's assertion that a synergistic effect was observed between an antibody with the CDRs of antibody B100 and trastuzumab or pertuzumab, none of the experimental data shown in Figures 1-5 appear to illustrate such an effect for the combination of B100 (or MAB270) paired with pertuzumab. Accordingly, the scope of the presently claimed invention is not congruent with any apparent synergistic effect illustrated by the Applicant.
For these reasons, the rejection is maintained.
(2)
Claims 1, 8, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Fischer (WO 2017/191327 A2; supra) in view of Lee (EP 2998319 A1; supra) as applied to claims 1, 3-6, 8, 13-16, and 18-19 above, and further in view of Voutsas (International Journal of Radiation Biology (2013) 89(5): 319-325; cited in PTO-892 mailed June 11, 2025).
The teachings of Fischer are recited in the 35 U.S.C. § 103 rejection above.
However, Fischer does not recite a pharmaceutical composition comprising antibody B100 further in combination with a second HER2 inhibitor (e.g., trastuzumab), further in combination with ionizing radiation.
The teachings of Lee are recited in the 35 U.S.C. § 103 rejection above.
Voutsas teaches that a single dose of 5 Gy gamma-irradiation induces HER2 overexpression in the human breast cancer cell lines (MDA-MB-321 and MDA-MB-435) having low basal levels of HER2 (e.g., Abstract; page 321, Results; Figures 1-2). Voutsas further illustrates that trastuzumab exerts greater antiproliferative effects on irradiated MDA-MB-231 and MDA-MD-435 breast cancer cells lines than one non-irradiated cell lines (e.g., page 321, Results; Figure 4). Voutsas concludes that irradiation-induced expression of HER2 in these cell lines renders them more susceptible to the antiproliferative effects of trastuzumab (e.g., Abstract; page 321, Results).
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to possess a pharmaceutical composition comprising the combination of trastuzumab and a second anti-HER2 antibody, e.g., the B100 antibody taught by Fischer, further in combination with ionizing radiation (e.g., gamma-irradiation), based on the collective teachings of Fischer, Lee, and Voutsas. The skilled artisan would have been motivated to do so because, as taught by Lee, many patients with HER2-positive cancer do not respond to trastuzumab monotherapy, and a combinatorial treatment comprising two anti-HER2 antibodies that each bind a separate epitope of HER2 is more effective than either antibody alone. The skilled artisan would have been motivated to further add ionizing radiation (e.g., gamma-irradiation) because, as taught by Voutsas, gamma-irradiation induces HER2 expression in breast cancer cell lines with low basal expression of HER2 and increases their sensitivity to treatment with trastuzumab. There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized that the anti-HER2 antibodies taught by Fischer (B100) and Lee (hz1E11) are functional equivalents in that both possess the same qualities of (1) binding specifically to HER2 at a different epitope than trastuzumab, and (2) potently inducing apoptosis of cancer cells, and it would thus have been obvious to try substituting hz1E11 with B100 in a HER2 combination therapy. In addition, one of ordinary skill in the art would have recognized the suitability of further adding gamma-irradiation for the purpose of further enhancing the therapeutic effect of trastuzumab in a HER2-positive cancer which might otherwise be less sensitive to treatment.
Response to Arguments
Applicant's arguments filed December 4, 2025 have been fully considered but they are not persuasive.
Applicant asserts that, as previously discussed for the rejection of Fisher in view of Lee, the combination of an anti-HER2 antibody with the CDRs of B100 and either trastuzumab or pertuzumab resulted in an unexpectedly synergistic effect, and there would have thus been no reasonable expectation of success combining the teachings of Fischer, Lee, and Voutsas (Remarks at pages 14-15).
Regarding Applicant's assertion regarding unexpected synergistic effects, reference is made to the Response above.
Regarding Applicant's assertion regarding reasonable expectation of success, it remains held that Voutsas teaches that gamma-irradiation increases treatment sensitivity to trastuzumab, and accordingly, would have reasonably been expected to enhance the therapeutic effect of a treatment regimen comprising trastuzumab, including trastuzumab in combination with another HER2 inhibiting agent (e.g., the B100 antibody of Fisher or the hz1E11 antibody of Lee).
Accordingly, the rejection is maintained.
Double Patenting (Maintained)
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.
(1)
Claims 1, 3-6, 13-16, and 18-19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 7-8, 12, 15, and 17-19 of U.S. Patent No. 11,091,561 in view of Lee (EP 2998319 A1; supra). This rejection has been updated to reflect Applicant's claim amendments.
The ‘561 patent claims a monoclonal antibody that specifically binds to HER2, or a fragment or derivative thereof that binds to HER2, denoted “B100”, which comprises a VH comprising the amino acid sequence of SEQ ID NO: 4 (which shares 100% identity to instant SEQ ID NO: 80 and comprises corresponding CDRs comprising the amino acid sequences of instant SEQ ID NO: 1-3, respectively) and a VL comprising an amino acid sequence of SEQ ID NO: 10 (which shares 100% identity to SEQ ID NO: 89 and comprises corresponding CDRs comprising the amino acid sequences of instant SEQ ID NO: 4-6, respectively), wherein the antibody is a humanized antibody (patented claims 1-4, 7-8, and 15), relevant to the antibody recited in instant claims 1 and 3-5. Relevant to instant claim 6, the antibody does not compete with trastuzumab in an epitope competition assay (patented claim 12). Patented claim 18 recites a pharmaceutical composition comprising a therapeutically effective amount of the B100 antibody of patented claim 1.
Relevant to instant claim 13, the ‘561 patent claims a method of treating a HER2-mediated disease that comprises administering to a subject in need thereof an antibody according to patent claim 1 or a pharmaceutical composition comprising the same to treat the HER2-mediated disease (patented claims 17 and 19).
However, the ‘561 patent does not teach a pharmaceutical composition comprising antibody B100 further in combination with a second HER2 inhibitor (e.g., trastuzumab), nor a method of treating a HER2-positive cancer by administering such a combination of anti-HER2 agents.
The teachings of Lee with respect to combination therapies for HER2-positive cancers, comprising trastuzumab in combination with a second anti-HER2 antibody, are recited in the 35 U.S.C. § 103 rejection above.
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to make and use a pharmaceutical composition comprising the combination of trastuzumab and a second anti-HER2 antibody, e.g., the B100 antibody taught in the ‘561 patent, in a method of treating a HER2-positive cancer, based on the collective teachings of the ‘561 patent and Lee. The skilled artisan would have been motivated to do so because, as taught by Lee, many patients with HER2-positive cancer do not respond to trastuzumab monotherapy, and a combinatorial treatment comprising two anti-HER2 antibodies that each bind a separate epitope of HER2 is more effective than either antibody alone. There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized that the anti-HER2 antibodies taught by the ‘561 patent (B100) and Lee (hz1E11) are functional equivalents in that both bind specifically to HER2 at a different epitope than trastuzumab. Accordingly, it would have been obvious to try substituting hz1E11 with B100 in a HER2 combination therapy.
(2)
Claims 1, 8, and 22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 7-8, 12, 15, and 17-19 of U.S. Patent No. 11,091,561 in view of Lee (EP 2998319 A1; supra) as applied to claims 1, 3-6, 13-16, and 18-19 above, and further in view of Voutsas (International Journal of Radiation Biology (2013) 89(5): 319-325; supra).
The teachings of the ‘561 patent are recited in the non-statutory double patenting rejection above.
However, the ‘561 patent does not recite a pharmaceutical composition comprising antibody B100 in combination with a second HER2 inhibitor (e.g., trastuzumab), further in combination with ionizing radiation.
The teachings of Lee and Voutsas are recited in the 35 U.S.C. § 103 rejection above.
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to possess a pharmaceutical composition comprising the combination of trastuzumab and a second anti-HER2 antibody, e.g., the B100 antibody taught in the ‘561 patent, further in combination with ionizing radiation (e.g., gamma-irradiation), based on the collective teachings of the ‘561 patent, Lee, and Voutsas. The skilled artisan would have been motivated to do so because, as taught by Lee, many patients with HER2-positive cancer do not respond to trastuzumab monotherapy, and a combinatorial treatment comprising two anti-HER2 antibodies that each bind a separate epitope of HER2 is more effective than either antibody alone. The skilled artisan would have been motivated to further add ionizing radiation (e.g., gamma-irradiation) because, as taught by Voutsas, gamma-irradiation induces HER2 expression in breast cancer cell lines with low basal expression of HER2 and increases their sensitivity to treatment with trastuzumab. There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized that the anti-HER2 antibodies taught in the ‘561 patent (B100) and Lee (hz1E11) are functional equivalents in that both bind specifically to HER2 at a different epitope than trastuzumab, and it would thus have been obvious to try substituting hz1E11 with B100 in a HER2 combination therapy. In addition, one of ordinary skill in the art would have recognized the suitability of further adding gamma-irradiation for the purpose of further enhancing the therapeutic effect of trastuzumab in a HER2-positive cancer which might otherwise be less sensitive to treatment.
(3)
Claims 1, 3-6, 13-16, and 18-19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8, 10-11, and 14-16 of U.S. Patent No. 12,129,307 in view of Lee (EP 2998319 A1; supra). This rejection has been updated to reflect Applicant's claim amendments.
The ‘307 patent claims 1 and 15 recite a fragment of derivative of the monoclonal antibody B100, which comprises a VH comprising the amino acid sequence of SEQ ID NO: 4 (which shares 100% identity to instant SEQ ID NO: 80 and comprises corresponding CDRs comprising the amino acid sequences of instant SEQ ID NO: 1-3, respectively) and a VL comprising an amino acid sequence of SEQ ID NO: 10 (which shares 100% identity to SEQ ID NO: 89 and comprises corresponding CDRs comprising the amino acid sequences of instant SEQ ID NO: 4-6, respectively), wherein the antibody fragment binds to a different epitope than trastuzumab (patented claims 8 and 10-11), relevant to instant claims 1 and 3-4. Patented claim 16 recites that the fragment is a humanized antibody fragment, relevant to instant claim 5. Patented claim 14 recites a pharmaceutical composition comprising the antibody fragment.
However, the ‘307 patent does not teach a pharmaceutical composition comprising antibody B100 further in combination with a second HER2 inhibitor (e.g., trastuzumab), nor a method of treating a HER2-positive cancer by administering such a combination of anti-HER2 agents.
The teachings of Lee with respect to combination therapies for HER2-positive cancers, comprising trastuzumab in combination with a second anti-HER2 antibody, are recited in the 35 U.S.C. § 103 rejection above.
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to make and use a pharmaceutical composition comprising the combination of trastuzumab and a second anti-HER2 antibody, e.g., the B100 antibody taught in the ‘307 patent, in a method of treating a HER2-positive cancer, based on the collective teachings of the ‘307 patent and Lee. The skilled artisan would have been motivated to do so because, as taught by Lee, many patients with HER2-positive cancer do not respond to trastuzumab monotherapy, and a combinatorial treatment comprising two anti-HER2 antibodies that each bind a separate epitope of HER2 is more effective than either antibody alone. There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized that the anti-HER2 antibodies taught by the ‘307 patent (B100) and Lee (hz1E11) are functional equivalents in that both bind specifically to HER2 at a different epitope than trastuzumab. Accordingly, it would have been obvious to try substituting hz1E11 with B100 in a HER2 combination therapy.
(4)
Claims 1, 8, and 22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8, 10-11, and 14-16 of U.S. Patent No. 12,129,307 in view of Lee (EP 2998319 A1; supra) as applied to claims 1, 3-6, 13-16, and 18-19 above, and further in view of Voutsas (International Journal of Radiation Biology (2013) 89(5): 319-325; supra).
The teachings of the ‘307 patent are recited in the non-statutory double patenting rejection above.
However, the ‘307 patent does not recite a pharmaceutical composition comprising antibody fragment B100 in combination with a second HER2 inhibitor (e.g., trastuzumab), further in combination with ionizing radiation.
The teachings of Lee and Voutsas are recited in the 35 U.S.C. § 103 rejection above.
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to possess a pharmaceutical composition comprising the combination of trastuzumab and a second anti-HER2 antibody, e.g., the B100 antibody fragment taught in the ‘307 patent, further in combination with ionizing radiation (e.g., gamma-irradiation), based on the collective teachings of the ‘307 patent, Lee, and Voutsas. The skilled artisan would have been motivated to do so because, as taught by Lee, many patients with HER2-positive cancer do not respond to trastuzumab monotherapy, and a combinatorial treatment comprising two anti-HER2 antibodies that each bind a separate epitope of HER2 is more effective than either antibody alone. The skilled artisan would have been motivated to further add ionizing radiation (e.g., gamma-irradiation) because, as taught by Voutsas, gamma-irradiation induces HER2 expression in breast cancer cell lines with low basal expression of HER2 and increases their sensitivity to treatment with trastuzumab. There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized that the anti-HER2 antibodies taught in the ‘307 patent (B100) and Lee (hz1E11) are functional equivalents in that both bind specifically to HER2 at a different epitope than trastuzumab, and it would thus have been obvious to try substituting hz1E11 with B100 in a HER2 combination therapy. In addition, one of ordinary skill in the art would have recognized the suitability of further adding gamma-irradiation for the purpose of further enhancing the therapeutic effect of trastuzumab in a HER2-positive cancer which might otherwise be less sensitive to treatment.
Response to Arguments (Combined)
Applicant's arguments filed December 4, 2025 have been fully considered but they are not persuasive.
Applicant acknowledges each of the rejections above and notes that “appropriate corrective action of filing a terminal disclaimer or distinguishing the claims once allowable subject matter is obtained” (Remarks at pages 15-16).
In response, Applicant’s request to hold the nonstatutory double patenting rejections in abeyance is denied. The rejections will remain in place until they are overcome by amendment, terminal disclaimer, or otherwise.
Citation of Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to Applicant's disclosure:
Bodyak (WO 2018/160538 A1) discloses pharmaceutical compositions comprising a HER2-targeted antibody-drug conjugate of the invention, an immune checkpoint inhibitor, and an additional agent such as trastuzumab, pertuzumab, or lapatinib, and therapeutic methods of use thereof (e.g., Abstract; ¶ 00151-00157).
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/Brad Duffy/Primary Examiner, Art Unit 1643