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
Claims 1-7, 9, 11, 26-32, 34-36, and 38-52 are pending in the instant application.
Claims 8, 10, and 33 have been canceled.
Claims 51-52 are new.
Claim Rejections and Objections Withdrawn
The rejections to claims 8, 10, and 33 is moot in view of claim cancelation.
The objection to claims 1, 26, and 38-39 is withdrawn in view of claim amendment.
The rejection to claims 1-9, 11, and 48-49 under 35 USC § 112(b) is withdrawn in view of claim amendment.
The rejection to claim 47 under 35 USC § 112(b) is withdrawn in view of Applicant’s argument that a person having ordinary skill in the art readily understands an immunohistochemical score of “>0 and <+1” (Arguments filed 6/17/2026, page 11, last paragraph). A claim interpretation is below as previously interpreted to promote compact prosecution in the previous Office Action.
The rejection to claims 1-7, 11, 26-32, 34-36, and 38-50 under 35 USC § 112(a) is withdrawn in view of claim amendment.
The rejection to claims 1-4, 6-7, 11, 26-29, 31-32, 36, 38-40, 44, 48 and 50 under 35 U.S.C. 102(a)(1) as being anticipated by US 20160333112 (Naito H et al.) is withdrawn in view of claim amendment.
The rejection to claims 1-7, 9, 26-32, 34-35, 38-42, 48, and 50-52 under 35 U.S.C. 102(a)(1) as being anticipated by NCT04784715 clinical trial is withdrawn in view of claim amendment.
The rejection to claims 1-7, 9, 11, 26-32, 34-36, and 38-50 under 35 USC § 103 is withdrawn in view of claim amendment.
The rejection to claims 1-7, 26-32, 35, 38-40, 48, and 50 under nonstatutory double patenting is withdrawn in view of claim amendment.
Claim Interpretation
Regarding instant claim 47, a score of “>0 and <+1” will be interpreted as low expression of HER2 wherein HER2 expression by immunohistochemistry staining is 0, but expression by other methods indicate the tumor as HER2-positive. US 20160333112 (Naito H et al.) taught classification of HER2 expression by immunohistochemistry staining, wherein 3+ was high expression, 2+ was moderate expression, and 1+ was low expression, and wherein if the score was 0 in this measurement method, tumor found HER2-positive by other measurement methods such as a measurement method using a flow cytometer was classified as low expressing tumor (page 102, paragraph 757).
Priority
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e). Failure to provide a certified translation may result in no benefit being accorded for the non-English application. The effective priority date is the filing date of PCT/JP2021/026932 filed on 7/19/2021 in the absence of a certified translation of JP2020-123564 filed on 7/20/2020.
Response to Arguments
Applicant argues a certified English translation of the priority document is submitted herewith. Thus, the effective priority date is the filing date of JP 2020-123564, July 20, 2020.
In response, Applicant's arguments filed 6/17/2026 have been fully considered but they are not persuasive. No translation has been received. Thus, the effective priority date is the filing date of PCT/JP2021/026932 filed on 7/19/2021.
Claim Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 112(a)
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 1-7, 11, 26-32, 35-36, 38-50 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.
Claims 1-7, 11, 26-32, 35-36, 38-50 describe the HER dimerization inhibitor in the composition via function rather than structure, wherein the claims require the HER2 dimerization inhibitor in the composition to be an antibody capable of binding to subdomain II of an extracellular domain of HER2 protein, but the prediction of CDR binding to the epitope is unpredictable. Pertuzumab was the only HER dimerization inhibitor capable of binding to subdomain II of an extracellular domain of HER2 protein tested.
Scope of the claimed genus
Claims 1-7, 11, 26-32, 35-36, 38-50 describe a pharmaceutical composition or a method wherein the pharmaceutical composition requires an anti-HER2 antibody-drug conjugate and a HER dimerization inhibitor, wherein the claims require the HER2 dimerization inhibitor in the composition to be an antibody capable of binding to subdomain II of an extracellular domain of HER2 protein.
State of the Relevant Art;
1) The prior art has taught HER2 dimerization can be inhibited via targeting of multiple epitopes of HER2. Junttila TT et al. (Cancer Cell 2009 15 (5) 429-440 reference of record) taught that the antibody trastuzumab inhibits the Ligand-Independent HER2/HER3 Interaction (Junttila, Fig. 3) and thus is a HER dimerization inhibitor. US 20160333112 (Naito H et al. reference of record) taught pertuzumab targets the extracellular domain II of HER2 and inhibits heterodimer formation (page 2, paragraph 11). Meng Y et al. (Oncogenesis 2016 5, e211 reference of record) taught: a) pertuzumab, which binds to ErbB2 near the center of domain II; and b) trastuzumab, which binds to the juxtamembrane region of ErbB2 domain IV, directly interfere with domain II- and domain IV-mediated heterodimerization contacts (abstract). Meng further taught the HER2 antibody, 3E10, binds to an epitope in domain III located opposite to the dimerization interfaces in domain II and domain IV of HER2 and inhibits HER2 heterodimerization via a mechanism that strikingly differs from trastuzumab and pertuzumab (abstract). Feldinger K et al. (Breast Cancer: Targets and Therapy 2015:7 147–162 reference of record) further taught the tyrosine kinase inhibitor neratinib was able to suppress ligand-stimulated HER2–HER3 dimers and could effectively disrupt preformed HER2–HER3 dimers (page 150, right column, second paragraph). Not all kinase inhibitors can inhibit HER2 dimerization though. Claus J et al. (Elife 2018 7:e32271. doi: 10.7554/eLife.32271. reference of record) taught lapatinib drives HER2-HER3 kinase domain heterocomplex formation (abstract). Thus, binding HER2 does not necessarily inhibit dimerization. A structure activity relationship is unknown in the prior art regarding what antibody structures are HER dimerization inhibitors capable of binding to the subdomain II of an extracellular HER2 protein. It is unpredictable to determine ligand dependent and ligand independent HER dimerization inhibitors based on the HER2 binding site.
It is well established in the art that the formation of an intact antigen-binding site in an antibody usually requires the association of the complete heavy and light chain variable regions of a given antibody, each of which comprises three CDRs (or hypervariable regions) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro et. al., Front. Immunol. 2018; 8:1751 reference of record (see Section “The IgG Molecule” in paragraph 1 and Figure 1). While affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (page 3 “The IgG Molecule, second and third paragraphs), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. E.g., id., (page 6 ending paragraph onto page 7). Chiu ML et al. (Antibodies 2019 8, 55, 1-80 reference of record) taught the antigen binding of antibodies often results in conformational changes in the contact surface areas of both the antibody and the antigen (page 5, first paragraph). Thus, the prediction of CDR binding to the epitope is difficult to predict. Chiu further taught antibody modeling has been shown to be accurate for the framework region sequences, but CDR modeling requires further development and improvements (page 6, second paragraph). Prediction of the structure of HCDR3 could not be accurately produced when given the Fv structures without their CDR-H3s (page 6, second paragraph). Chiu taught the quality of antibody structure prediction, particularly regarding CDR-H3, remains inadequate, and the results of antibody–antigen docking are also disappointing (page 11, paragraph 2).
Summary of Species disclosed in the original specification
Pertuzumab was the only HER dimerization inhibitor tested in the instant specification;
Pertuzumab was the only HER dimerization inhibitor capable of binding to subdomain II of an extracellular domain of HER2 protein tested in the instant specification;
Conclusion
The Applicant does not have written description for a genus of species of HER dimerization inhibitors, wherein the HER2 dimerization inhibitor is an antibody capable of binding to subdomain II of an extracellular domain of HER2 protein in claims 1-7, 11, 26-32, 35-36, 38-50. The prediction of CDR binding to the epitope is unpredictable and a structure activity relationship is not disclosed for what antibodies can or cannot bind to subdomain II of the extracellular domain of HER2 protein and inhibitor dimerization. Pertuzumab was the only HER dimerization inhibitor capable of binding to subdomain II of an extracellular domain of HER2 protein tested.
Response to Arguments
As reflected by independent claims 1 and 26, the pending claims recite, in part, a HER dimerization inhibitor, "wherein the HER dimerization inhibitor is an antibody capable of binding to subdomain II of an extracellular domain of HER2 protein." An "antibody" is a description by structure, and such subject matter was indeed described in the specification as filed in such a way as to reasonably convey to one skilled in the relevant art that the inventor, at the time the application was filed, had possession of the claimed invention.
As described in paragraph [0005] of the Specification as filed, antibodies capable of binding to subdomain II of an extracellular domain of HER2 protein are understood to inhibit dimerization of HER2 and HER3 proteins, thereby inhibiting ligand-stimulated phosphorylation of HER2 and the activation of both PBK-Akt and MAPK kinases downstream, thus suppressing cell proliferation. Pertuzumab is listed as a representative example of an antibody that binds to sub domain II of the extracellular domain of the HER2 protein and inhibits HER dimerization, and a person skilled in the art could readily identify and/or screen relevant antibodies that bind the same target using routine methods.
Applicant argues that method is related to the recent decision by the Federal Circuit Authority, Teva Pharmaceuticals International GmbH v. Eli Lilly and Company, No. 2024-1094 (Fed. Cir. April 16, 2026), further supports the adequacy of the written description here. In Teva, the court reversed a judgment of invalidity for claims directed to methods of treating headache using a genus of humanized anti-CGRP antagonist antibodies, even though the specification disclosed only one humanized species. The court held that, where a claim "pertains to a well-known genus that is not, itself, the invention," adequate written description may be found in the specification read together with the background knowledge in the art. Id, slip op. at 9; see also Ajinomoto Co. v. ITC, 932 F.3d 1342, 1359 (Fed. Cir. 2019); In re Hersch/er, 591 F.2d 693, 700-01 (CCPA 1979). The same reasoning applies here regarding the method claims: the claimed subject matter is not the HER dimerization inhibitor itself, but the therapeutic use of such an inhibitor in combination with the recited antibody-drug conjugate. Pertuzumab is one example of such a HER dimerization inhibitor that was known prior to the filing date of the present application. Accordingly, under Teva, the specification's disclosure of pertuzumab as one example of a HER dimerization inhibitor, "wherein the HER dimerization inhibitor is an antibody capable of binding to subdomain II of an extracellular domain of HER2 protein" satisfies the written description requirement.
In response, Applicant's arguments filed 6/17/2026 have been fully considered but they are not persuasive. As described above, a structure activity relationship is unknown in the prior art regarding what antibody structures are HER dimerization inhibitors capable of binding to the subdomain II of an extracellular HER2 protein and prediction of CDR binding to the epitope is difficult to predict.
The fact pattern and corresponding analysis described in Teva for “the headache patents” are materially distinct from that of the instant application and claims. For reference, the representative claim at issue in Teva was directed to “A method for reducing incidence of or treating headache in a human, comprising administering to the human an effective amount of an anti-CGRP antagonist antibody, wherein said anti-CGRP antagonist antibody is a . . . humanized monoclonal antibody.” Teva at pages 3-4. With respect to the instantly claimed invention, the independent claims at issue are drawn to: a) a pharmaceutical composition in claim 1; or b) a method of treating cancer comprising administering an anti-HER2 ADC and a HER2 dimerization inhibitor in combination to a subject in need thereof wherein the ADC comprises an anti-HER2 antibody conjugated to a drug linker represented by the formula
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wherein A in the formula represents a connecting position to the anti-HER2 antibody and wherein the HER dimerization inhibitor is an antibody capable of binding to subdomain II of an extracellular domain of HER2 protein in claim 26. It is also noted that the written description requirement takes into consideration not only the content of the Applicant's disclosure but also the level of skill and knowledge in the art as well as the predictability of the art at the time of filing of the instantly claimed invention. See MPEP §§ 2161 and 2163. The analysis in Teva notes that the disclosures of the headache patents cited prior art demonstrating that anti-CGRP antagonist antibodies were ‘known in the art’ and also disclosed prior art methods for humanizing antibodies. Teva at page 13. Importantly, the Teva decision also recites, “Although the specification disclosed just one humanized anti-CGRP antagonist antibody, it also disclosed several murine versions and prior-art methods of humanization—against a backdrop of anti-CGRP antagonist antibodies (and methods of making them) being well known and humanization being routine. And, critically, a skilled artisan would have understood from the specification that all humanized anti-CGRP antagonist antibodies treat headache” (emphasis added). Teva at page 13.
A search of the prior art suggests that the genus of antibodies that specifically bind to subdomain II of an extracellular domain of HER2 protein was less characterized compared to anti-CGRP antibodies, at the time of filing of the instantly claimed invention. While the prior art has identified that pertuzumab has that capability, wherein US 20160333112 (Naito H et al.) taught pertuzumab targets the extracellular domain II of HER2 and inhibits heterodimer formation (page 2, paragraph 11), the prior art lacks a large genus of species. The Applicant only discloses pertuzumab can perform the function of both binding subdomain II of an extracellular domain of HER2 protein and inhibiting dimerization. WO 2011/147982 (De Goeij B et al.) attempted to identify HER2 therapeutic antibodies and identified 0 that bind the subdomain II of HER2
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in comparison to other HER2 domains (‘982 page 73 Table 12).
Further, a person having ordinary skill in the art would not expect that all antibodies that bind to the subdomain II of an extracellular domain of HER2 protein effectively treat cancer based on the Applicants disclosure and the prior art. WO 2009/055074 (Gill D et al.) taught HER-2 binding antibodies wherein Fig. 51 taught the antibody HER116 comprised a binding site within the CR1 domain, which is subdomain II; and was ineffective at treating cancer in a subject, wherein subjects administered the subdomain II binding antibody HER116 demonstrated a tumor growth rate and mortality similar to control IgG (Fig. 46 and 47)
The state and predictability of the relevant art further suggest antibody binding and blocking are not always seen in combination, the following excerpt from the Supreme Court’s decision in Amgen, Inc. et al. v. Sanofi et al., No. 21-757, Decided May 18, 2023), at page 3, is highlighted here:
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Based on this understanding of the state and predictability of the art at the time the instantly invention was filed, the skilled artisan would have understood that (1) the claimed genus of antibodies set forth in the instant claims is not a well-known genus (unlike in Teva), and (2) not all antibodies which bind to the subdomain II of HER2 would also be expected to possess the required functional activity of effectively treating cancer.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or it may be satisfied by the disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. “Functional” terminology may be used “when the art has established a correlation between structure and function” but “merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing one has invented a genus and not just a species. Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010).
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). “[A] sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A “representative number of species” means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention. For example, the Federal Circuit has found that possession of a mouse antibody heavy and light chain variable regions provides a structural "stepping stone" to the corresponding chimeric antibody, but not to human antibodies. Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875 (Fed. Cir. 2011).
Amgen Inc. v. Sanofi, Aventisub LLC, 872 F.3d 1367 (Fed. Cir. 2017) supported previous decisions (Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341 (Fed. Cir. 2011); AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc., 759 F.3d 1285 (Fed. Cir. 2014)) that defining an antibody solely by what it binds does not satisfy the written description requirement, stating that this would allow patentees to “claim antibodies by describing something that is not the invention, i.e., the antigen”. Thus, claiming an antibody by describing the invention by what it does (function) rather than what it is (structure) is invalid. This can be overcome if a relevant number of species with structure/function correlation is known to the art or present in the specification. See also pages 206-208 of Deng (mAbs (2018) 10(2): 204-209; cited in IDS).
Thus, The Applicant does not have written description for a genus of species of HER dimerization inhibitors, wherein the HER2 dimerization inhibitor is an antibody capable of binding to subdomain II of an extracellular domain of HER2 protein in claims 1-7, 11, 26-32, 35-36, 38-50. The prediction of CDR binding to the epitope is unpredictable and a structure activity relationship is not disclosed for what antibodies can or cannot bind to subdomain II of the extracellular domain of HER2 protein and inhibitor dimerization. Pertuzumab was the only HER dimerization inhibitor capable of binding to subdomain II of an extracellular domain of HER2 protein tested.
Claim Rejections – 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-7, 9, 26-32, 34-35, 38-42, 48, and 50-52 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by NCT04784715 clinical trial. (https://clinicaltrials.gov/study/NCT04784715?tab=history&a=4#version-content-panel 06/2021 reference of record).
Regarding instant claims 1-7, 9, 26-32, 34-35, 38-42, 48, and 50, NCT04784715 taught a method of treating patients with a combination of Trastuzumab deruxtecan (T-DXd) with pertuzumab (page 11, Arm B), wherein the patients have HER2-positive (IHC 3+ or ISH+), metastatic breast cancer (page 9, detailed description). This method would naturally exert a significantly superior antitumor effect than single administration of the anti-HER2 antibody-drug conjugate and a synergistic antitumor effect (instant claims 48 and 50).
This meets the claim limitations of 1-7, 9, 26-32, 34-35, 38-42, 48, and 50.
Response to Arguments
Applicant argues regarding the rejection over the NCT04784715 clinical trial, this publication does not qualify as prior art against the present application. The NCT04784715 clinical trial has an earliest submission of March 2, 2021, which was reported as "first posted" on March 5, 2021. As discussed above with regard to priority, the pending claims have an effective filing date of July 20, 2020, approximately 8 months prior to the publication of the NCT04784715 clinical trial. Thus, the NCT04784715 clinical trial does not qualify as prior art under 35 U.S.C. § 102(a)(1)
and Applicant respectfully requests reconsideration and withdrawal of the related anticipation rejection.
In response, Applicant's arguments filed 6/17/2026 have been fully considered but they are not persuasive. No translation has been received. Thus, the effective priority date is the filing date of PCT/JP2021/026932 filed on 7/19/2021 which is after the NCT04784715 clinical trial.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
The 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.
Claims 1-7, 9, 11, 26-32, 34-36, and 38-52 are rejected under 35 U.S.C. 103 as being unpatentable over US 20160333112 (Naito H et al. reference of record) and Scheuer W et al. (Cancer Res 2009 69(24) 9330–9336, IDS reference) and evidenced by ADC Review (https://www.adcreview.com/trastuzumab-deruxtecan-drug-description/ reference of record) and SciFinder Trastuzumab deruxtecan (CAS RN 1826843-81-5 retrieved 2025 reference of record).
Regarding claims 1-7, 9, 11, 26-32, 34-36, and 38-52, Naito taught a method of treating breast cancer that expressed HER2 in a subject comprising administering a pharmaceutical composition of the anti-HER2 trastuzumab linked exatecan ADC of example 50 was more effective than trastuzumab at inhibiting HER2 expressing breast tumor growth in vivo (Fig. 8 and 9).
Regarding claims 1-7, 9, 11, 26-32, 34-36, and 38-52, Naito taught administration of a pharmaceutical composition of the anti-HER2 ADC and pertuzumab administered to an individual simultaneously with, separately from, or subsequently to the antibody-drug conjugate (page 32, paragraph 384). Regarding claims 8 and 33, Naito taught pertuzumab targets the extracellular domain II of HER2 and inhibits heterodimer formation (page 2, paragraph 11).
Regarding claims 41-43 and 46, Naito taught the anti-HER2 trastuzumab linked exatecan ADC of example 50 was effective in cancers wherein the cancer expression as measured by IHC is 3+, which is HER2 overexpressing cancer (page 103, paragraphs 780-785 and Figures 12-13), 2+ (page 102, paragraphs 764-766 and Figure 8), and 1+ (pages 102-103, paragraph 767-769 and Fig.9).
Regarding claims 44-47, Naito taught the anti-HER2 trastuzumab linked exatecan ADC of example 50 was effective at inhibiting breast tumor growth in vivo with low HER2 expression, while trastuzumab and a different ADC of trastuzumab linked emtansine were not effective (pages 102-103, paragraph 767-769 and Fig.9). Naito taught classification of HER2 expression by immunohistochemistry staining, wherein 3+ was high expression, 2+ was moderate expression, and 1+ was low expression, and wherein if the score was 0 in this measurement method, tumor found HER2-positive by other measurement methods such as a measurement method using a flow cytometer was classified as low expressing tumor (page 102, paragraph 757). Regarding claims 1-11, 26-36, and 38-50, Naito taught the anti-HER2 trastuzumab linked exatecan ADC exhibited a dose dependent antitumor effect and did not cause weight loss in vivo (page 102, paragraph 759).
Regarding the structure and sequence of the ADC, Regarding claims 1-7, 9, 11, 26-32, 34-36, and 38-52, Naito taught an anti-HER2 ADC (abstract), wherein the antibody trastuzumab was conjugated to a linker with the structure:
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(page 99, paragraph 717) and wherein the ADC of example 50 had an average number of 7.8 drug molecules conjugated per antibody (page 100, paragraph 724, example 50) and is evidenced by ADC Review to have the same drug linker as trastuzumab deruxtecan (ADC Review, page 3, top picture). Regarding claim 1, Naito taught the anti-HER2 ADC conjugated to the drug-linker via a thioether bond between the antibody and linker (page 25, paragraph 318).
Regarding claims 2-6, Naito taught the anti-HER2 ADC targeting antibody as trastuzumab (page 10, paragraph 109, Figure 1 and 2), wherein:
1) the antibody comprises a heavy chain consisting of the amino acid sequence of SEQ ID NO: 1 and a light chain consisting of the amino acid sequence of SEQ ID NO: 2, which is identical to trastuzumab deruxtecan as evidenced by SciFinder (SciFinder, pages 2-3, Sequence Details);
2) the antibody of 1) wherein the antibody lacks a lysine residue at the carboxyl terminus of the heavy chain; or
3) the antibody comprised a heavy chain consisting of an amino acid sequence consisting of amino acid residues 1 to 449 of SEQ ID NO: 1 and a light chain consisting of an amino acid sequence consisting of amino acid residues 1 to 214 of SEQ ID NO: 2 (pages 9-10, paragraphs 98-100). Regarding claim 4, the Naito antibody of SEQ ID NO:1 comprises a heavy chain variable region VH consisting of the amino acid sequence of 1-120 and a IgG1 constant region and from 121-450. Regarding claims 4-5, the Naito antibody of SEQ ID NO:2 comprises a light chain variable region VL consisting of the amino acid sequence of 1-107 and a IgG1kappa constant region and from 108-214. Regarding claim 5, Naito taught it is known that a lysine residue at the carboxyl terminus of the heavy chain of an antibody produced in a cultured mammalian cell is deleted, however, such deletion and modification of the heavy chain sequence do not affect the antigen-binding affinity and the effector function (the activation of a complement, the antibody-dependent cellular cytotoxicity, etc.) of the antibody (page 16, paragraphs 218).
While Naito taught a method of treating cancer wherein the HER2 ADC conjugated to Formula I is administered in combination with the HER2 dimerization inhibitor pertuzumab among several embodiments, this embodiment is further obvious and supported in view of Scheuer.
Regarding claims 1-7, 9, 11, 26-32, 34-36, and 38-52, Scheuer taught an effective method of cancer treatment wherein subjects with HER2 positive breast cancer were administered a pharmaceutical composition comprising trastuzumab in combination with pertuzumab, wherein combining trastuzumab and pertuzumab induced strongly enhanced antitumor activity compared with either agent alone (Table 1 and Fig. 1B), resulting in tumor regression and, in 6 of 10 subjects, complete tumor remission (Table 1). Regarding claim 49, Scheuer taught combination treatment of trastuzumab and pertuzumab to subjects with HER2 expressing tumors resulted in a response that was effective compared to trastuzumab alone which was ineffective for complete tumor regression (Table 1 and Fig. 1B).
Regarding instant claims 1-7, 9, 11, 26-32, 34-36, and 38-44, 46, 48-52, it would have been obvious for a person having ordinary skill in the art to take the method of treating a subject with breast cancer with low or overexpressed HER2 expression, or HER2 IHC expression of 1+, 2+, or 3+ comprising administering a subject an anti-HER2 targeting ADC conjugated to exatecan of Naito example 50, wherein Naito further taught the antibody comprises either: i) a heavy chain of SEQ ID NO: 1 and a light chain of SEQ ID NO: 2; or ii) consists of a heavy chain of amino acid residues 1 to 449 of SEQ ID NO: 1 and a light chain of amino acid residues 1 to 214 of SEQ ID NO: 2 – and: 1) further simultaneously or separately administer pertuzumab as taught by Naito; and 2) further treat cancer untreatable with administration of the anti-HER2 antibody-drug conjugate alone with pertuzumab in combination
This is obvious because Naito taught combination treatment with pertuzumab and: 1) and 2) pharmaceutical compositions comprising trastuzumab in combination with pertuzumab induce strongly enhanced antitumor activity compared with either agent alone, resulting in tumor regression and complete tumor remission as taught by Scheuer; and 2) Scheuer taught combination treatment of trastuzumab and pertuzumab to subjects with HER2 expressing tumors resulted in a response that was more effective compared to trastuzumab alone which was ineffective for complete tumor regression. Combinations comprising trastuzumab and pertuzumab are known to be more effective and the ADC of Naito example 50 comprises trastuzumab and thus would also be expected to be effective more effective when combined with pertuzumab. Further, the trastuzumab comprising ADC of Naito example 50 is known to be more effective than trastuzumab alone, thus combinations of the ADC with pertuzumab would be also be expected to be more effective when used in combination.
There is a reasonable expectation of success because: 1) and 2) pharmaceutical compositions comprising trastuzumab in combination with pertuzumab induce strongly enhanced antitumor activity compared with either agent alone, resulting in tumor regression and complete tumor remission as taught by Scheuer; and 2) Scheuer taught combination treatment of trastuzumab and pertuzumab to subjects with HER2 expressing tumors resulted in a response that was more effective compared to trastuzumab alone which was ineffective for complete tumor regression.
Combinations comprising trastuzumab and pertuzumab are known to be more effective and the ADC of Naito example 50 comprises trastuzumab and thus would also be expected to be effective more effective when combined with pertuzumab. Further, the trastuzumab comprising ADC of Naito example 50 is known to be more effective than trastuzumab alone, thus combinations of the ADC with pertuzumab would be also be expected to be more effective when used in combination.
This would produce a method of treating a subject with breast cancer (instant claims 38-40) with low or overexpressed HER2 expression, or HER2 IHC expression of 1+, 2+, or 3+ (instant claims 41-44 and 46), wherein the method is untreatable with administration of an anti-HER2 antibody-drug conjugate alone (instant claim 49), comprising simultaneously (instant claims 11 and 36) or separately (instant claim 35) administering a pharmaceutical composition of the anti-HER2 ADC linked exatecan of Naito example 50 and the extracellular domain II targeting HER2 heterodimer antibody inhibitor pertuzumab (instant claims 9 and 34) in combination, wherein the drug linker is represented by the formula
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, wherein the anti-HER2 ADC is conjugated to the drug-linker via a thioether bond between the antibody and linker (instant claims 1 and 26), wherein the drug-linker conjugated per antibody molecule is 7.8, which is between 7 and 8 (instant claims 6 and 31), wherein the anti-HER2 antibody is: i) a heavy chain of SEQ ID NO: 1 and a light chain of SEQ ID NO: 2 with an identical sequence to instant SEQ ID NO:1 and 2 and is the same as trastuzumab deruxtecan (instant claims 4, 7, 29, 32, and 51-52); or ii) consists of a heavy chain of amino acid residues 1 to 449 of SEQ ID NO: 1 and a light chain of amino acid residues 1 to 214 of SEQ ID NO: 2 with an identical sequence to instant SEQ ID NO:11 and SEQ ID NO:2 (instant claims 5 and 30), wherein both antibodies comprise a light and heavy chain that: a) consist of identical amino acids for the CDRH1-3 to amino acid residues 26 to 33, 51 to 58, and 97-109 of instant SEQ ID NO: 1 and CDRL1-3 of amino acid residues 27 to 32, 50 to 52, and 89-97 of instant SEQ ID NO: 2 as defined by IMGT numbering (instant claims 2 and 27); and b) consist of a heavy chain variable region amino acid sequence identical to amino acids 1 to 120 of instant SEQ ID NO:9 and light chain variable region of amino acid residues 1 to 107 of instant SEQ ID NO:10 (instant claims 3 and 28). This method would naturally exert a significantly superior antitumor effect than single administration of the anti-HER2 antibody-drug conjugate and a synergistic antitumor effect (instant claims 48 and 50).
Regarding instant claims 45 and 47, it would have been obvious for a person having ordinary skill in the art to take the method above of Naito and Scheuer above – and modify it to treat low HER2 expressing cancers wherein: 1) the cancer expressed low HER2 expression and the score was 0 by immunohistochemistry, but tumor was found HER2-positive by other measurement methods such as a measurement method using a flow cytometer; or 2) wherein the HER2 low-expressing cancer is cancer given a score of 2+ for the expression of HER2 in an immunohistochemical method and determined as negative for the expression of HER2 in an in situ hybridization method.
This is obvious because: 1) Naito taught the ADC of Naito example 50 is known to be effective in treating low HER2 expressing tumors and a cancer with low HER2-expression would still be targeted by the ADC of Naito example 50 and pertuzumab. Additionally, Naito taught the ADC of Naito example 50 was effective in immunohistochemically categorized HER2 expression of 2+. Further, Naito taught classification of HER2 expression by immunohistochemistry staining, wherein if the score was 0 in this measurement method, tumor found HER2-positive by other measurement methods such as a measurement method using a flow cytometer was classified as low expressing tumor. Thus, Naito recognized that the ADC of Naito example 50 could be used as a treatment for a low HER2 expressing tumor.
There is a reasonable expectation of success because: 1) Naito taught the ADC of Naito example 50 is known to be effective in treating low HER2 expressing tumors and a cancer with low HER2-expression would still be targeted by the ADC of Naito example 50 and pertuzumab. Additionally, Naito taught the ADC of Naito example 50 was effective in immunohistochemically categorized HER2 expression of 2+. Further, Naito taught classification of HER2 expression by immunohistochemistry staining, wherein if the score was 0 in this measurement method, tumor found HER2-positive by other measurement methods such as a measurement method using a flow cytometer was classified as low expressing tumor. Thus, Naito recognized that the ADC of Naito example 50 could be used as a treatment for a low HER2 expressing tumor. Thus, the combination would be expected to be effective in these low HER2 expressing tumors because the target is still present.
This would produce a method of treating a subject with breast cancer with low HER2 expression, wherein: 1) the cancer expressed low HER2 expression and the score was 0 by immunohistochemistry, but tumor was found HER2-positive by other measurement methods such as a measurement method using a flow cytometer or treat (instant claim 47); 2) wherein the HER2 low-expressing cancer is cancer given a score of 2+ for the expression of HER2 in an immunohistochemical method and determined as negative for the expression of HER2 in an in situ hybridization method (instant claim 45); or 3) HER2 IHC expression of 1+, wherein the method is untreatable with administration of an anti-HER2 antibody-drug conjugate alone, comprising simultaneously or separately administering a pharmaceutical composition of the anti-HER2 ADC linked exatecan of Naito example 50 and the extracellular domain II targeting HER2 heterodimer antibody inhibitor pertuzumab in combination, wherein the drug linker is represented by the formula
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, wherein the anti-HER2 ADC is conjugated to the drug-linker via a thioether bond between the antibody and linker, wherein the drug-linker conjugated per antibody molecule is 7.8, which is between 7 and 8, wherein the anti-HER2 antibody is: i) a heavy chain of SEQ ID NO: 1 and a light chain of SEQ ID NO: 2 with an identical sequence to instant SEQ ID NO:1 and 2 and is the same as trastuzumab deruxtecan; or ii) consists of a heavy chain of amino acid residues 1 to 449 of SEQ ID NO: 1 and a light chain of amino acid residues 1 to 214 of SEQ ID NO: 2 with an identical sequence to instant SEQ ID NO:11 and SEQ ID NO:2, wherein both antibodies comprise a light and heavy chain that: a) consist of identical amino acids for the CDRH1-3 to amino acid residues 26 to 33, 51 to 58, and 97-109 of instant SEQ ID NO: 1 and CDRL1-3 of amino acid residues 27 to 32, 50 to 52, and 89-97 of instant SEQ ID NO: 2 as defined by IMGT numbering; and b) consist of a heavy chain variable region amino acid sequence identical to amino acids 1 to 120 of instant SEQ ID NO:9 and light chain variable region of amino acid residues 1 to 107 of instant SEQ ID NO:10. This method would naturally exert a significantly superior antitumor effect than single administration of the anti-HER2 antibody-drug conjugate and a synergistic antitumor effect.
Response to Arguments
Applicant argues Naito discloses a generic drug-linker structure as an element of an ADC that includes a wide range of variables and potential structures. See, e.g., Naito, paragraph [0057]. Naito also describes pharmaceutical compositions of the disclosure may contain at least one other cancer treating agent other than the ADC. However, this list includes numerous different classes of anticancer agents with varying mechanisms of action. See Naito, paragraph [0384]. Thus, Naito discloses literally millions of different combinations of ADCs and anticancer agents such that the size of the genus is indisputably large. Further, nothing in Naito expressly suggests selecting the particular ADC of the pending claims, comprising a specific drug-linker, and pertuzumab out of the veritable sea of combinations. Rather, the specific selections relied upon by the Office Action are based entirely on improper hindsight as there would be no reason, absent the guidance of the present application, to pick the specifically recited combination from the disclosure of Naito, much less with any reasonable expectation of success. Indeed MPEP § 2144.08(11) specifically instructs when, as here, the cited art discloses a genera that encompasses a more specifically claimed genus, the Examiner must consider, among other things: (1) the size of the genus; (2) the express teachings of the references; and (3) any teachings to support selection of the species. Here, a person of ordinary skill in the art would not have had any reason to use an ADC and pertuzumab in a pharmaceutical composition or method as claimed from the general disclosure of Naito.
Scheuer cannot compensate for this deficiency. While Scheuer indeed describes an enhanced antitumor activity of trastuzumab and pertuzumab, there is nothing in Scheuer that teaches or suggests combining pertuzumab with any ADC, much less an ADC of the pending claims. In fact, Scheuer does not mention ADCs at all. For this reason alone, Scheuer cannot and does not provide a motivation to select and use the ADC of the pending claims out of the enormous genus of ADCs described by Naito in combination with pertuzumab out of the many "other" anti-cancer agents of Naito, much less with any reasonable expectation of success.
Further, Scheuer itself describes that "[t]he strongly enhanced activity of trastuzumab and pertuzumab is likely attributable to their alternative, differing mechanisms of action." Scheuer, page 9335, col. II, paragraph 2. As is readily understood by those of ordinary skill in the art and discussed above, ADCs and their corresponding unconjugated ("naked") antibody do not have the same mechanism of action. In the present case, the anti-HER2 antibody as a partial element of the ADC delivers the topoisomerase I inhibitor payload that exerts an anti-tumor effect based on its topoisomerase I inhibition activity. See, e.g., Specification as filed, paragraph [0060]. Meanwhile, Scheuer explains that a "major mechanism of action" of naked trastuzumab is via activation of antibody-dependent cellular cytotoxicity. See Scheuer, page 9335, col. I, paragraph 2. Thus, as the strongly enhanced anti tumor activity of trastuzumab and pertuzumab is attributable to their differing mechanisms of action, one of ordinary skill in the art would not be motivated to substitute trastuzumab with a ADC with a different mechanism of action and reasonably expect an improved antitumor activity in combination with pertuzumab, or any other HER dimerization inhibitor, wherein the HER dimerization inhibitor is an antibody capable of binding to subdomain II of an extracellular domain of HER2 protein as recited in the pending claims. Accordingly, Scheuer would not and could not motivate a person of ordinary skill in the art to reach the presently claimed combination or methods, much less with a reasonable expectation of success. For at least these many reasons, the cited references, either alone or in combination, fail to establish a prima facie case of obviousness. As such, Applicant respectfully requests reconsideration and withdrawal of the subject rejection.
In response, Applicant's arguments filed 6/17/2026 have been fully considered but they are not persuasive.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Regarding: i) Naito discloses literally millions of different combinations of ADCs; ii) nothing in Naito expressly suggests selecting the particular ADC of the pending claims, comprising a specific drug-linker, and pertuzumab out of the veritable sea of combinations; iii) the cited art discloses a genera that encompasses a more specifically claimed genus; iv) Scheuer that teaches or suggests combining pertuzumab with any ADC:
The obvious rational above relies on Naito and Scheuer. As described above:
Naito taught an effective method of treating breast cancer that expressed HER2 in a subject comprising administering a pharmaceutical composition of the anti-HER2 trastuzumab linked exatecan ADC of example 50 was more effective than trastuzumab at inhibiting HER2 expressing breast tumor growth in vivo (Fig. 8 and 9). Naito further taught administration of a pharmaceutical composition of the anti-HER2 ADC and pertuzumab administered to an individual simultaneously with, separately from, or subsequently to the antibody-drug conjugate (page 32, paragraph 384). Naito taught pertuzumab targets the extracellular domain II of HER2 and inhibits heterodimer formation (page 2, paragraph 11); and
Additionally, Scheuer taught an effective method of cancer treatment wherein subjects with HER2 positive breast cancer were administered a pharmaceutical composition comprising trastuzumab in combination with pertuzumab, wherein combining trastuzumab and pertuzumab induced strongly enhanced antitumor activity compared with either agent alone (Table 1 and Fig. 1B), resulting in tumor regression and, in 6 of 10 subjects, complete tumor remission (Table 1). Scheuer taught combination treatment of trastuzumab and pertuzumab to subjects with HER2 expressing tumors resulted in a response that was effective compared to trastuzumab alone which was ineffective for complete tumor regression (Table 1 and Fig. 1B).
Thus, the prior art has taught treatment of breast cancer with a combination of trastuzumab and pertuzumab are effective and that the combination is more effective than trastuzumab alone. The prior art has also taught when trastuzumab is conjugated to a drug with the structure:
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that it is more effective than trastuzumab at treating cancer. It would be obvious to combine the trastuzumab drug conjugate with pertuzumab as described in the obvious rational above.
In response to applicant's argument that there is nothing in Scheuer that teaches or suggests combining pertuzumab with any ADC, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
Regarding i) Scheuer itself describes that "[t]he strongly enhanced activity of trastuzumab and pertuzumab is likely attributable to their alternative, differing mechanisms of action." Scheuer, page 9335, col. II, paragraph 2; and ii) As is readily understood by those of ordinary skill in the art and discussed above, ADCs and their corresponding unconjugated ("naked") antibody do not have the same mechanism of action:
The Examiners respectfully disagrees. Conjugation of an effective cancer drug to trastuzumab would not be expected to render pertuzumab combination treatment ineffective. Further, the prior art has previously shown binding activity to HER2 and ADCC activity of DS-8201a were comparable with unconjugated anti-HER2 antibody (abstract) in Ogitani et al. (Clinical Cancer Research, Vol. 22, No. 20, October 15, 2016, pp. 5097-5108, IDS reference), wherein DS-8201a has the structure of Naito above and is also known as trastuzumab deruxtecan. Thus, the trastuzumab ADCC activity is still present in Naito Example 50 above and has an additional benefit from the drug conjugate. Thus, the combination in the obvious rational above is obvious with a reasonable expectation of success.
Conclusion
No claims are allowable.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOHN J SKOKO III whose telephone number is (571)272-1107. The examiner can normally be reached M-F 8:30 - 5:00.
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/J.J.S./Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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