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 1-11, 26-36, and 38-50 are pending in the instant application.
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.
Objections to the Claims
Claims 1, 26, and 38-39 are objected to because of the following informalities:
Claims 1 and 26 are grammatically incorrect. An example to overcome the objection is to exchange the last two lines of the claims with: --- is conjugated to the anti-HER2 antibody via a thioether bond, wherein A represents a connecting bond to an anti-HER2 antibody.---
Claims 38-39 list Paget’s disease as a form of cancer, but there are two types of Paget’s disease, wherein “Paget's disease of the breast” is a cancer, while “Paget’s disease” is a bone metabolic disorder. Amend the claim to “Paget's disease of the breast” for clarity.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-11 and 47-49 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.
Regarding instant claim 1, it is unclear if the claimed pharmaceutical composition consists or comprises of an anti-HER2 antibody-drug conjugate and a HER dimerization inhibitor. Thus, the claim is indefinite. Claims 2-11 further include the indefinite subject matter and are also rejected.
To promote compact prosecution, claims 1-11 will be interpreted as directed to a pharmaceutical composition comprising an anti-HER2 antibody-drug conjugate and a HER dimerization inhibitor.
Regarding instant claim 47, it is unclear what the expression level of HER2 is in the cancer when the immunohistochemical expression is >0 and <1+. 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). Thus, HER2 immunohistochemical expression of >0 and <1+ is indefinite.
To promote compact prosecution, HER2 immunohistochemical expression of >0 and <1+ will be interpreted as low HER2 expression 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.
Regarding instant claims 48-49, it is unclear if the claim is limited to a single dose administration of the anti-HER2 antibody-drug conjugate or administration of the anti-HER2 antibody-drug conjugate alone. Thus, the claim is indefinite.
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 1-8, 10-11, 26-36, 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, 10-11, 26-32, 35-36, 38-50 describe the HER dimerization inhibitor in the composition via function rather than structure, wherein the claim requires a HER dimerization inhibitor, but it is unpredictable all of the structures that are able to block HER dimerization. Pertuzumab was the only HER dimerization inhibitor tested;
Claims 8 and 33 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; and
Scope of the claimed genus
Claims 1-7, 10-11, 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;
Claims 8 and 33 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 claim requires 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) and 2) 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) 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.) 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) 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) 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.) 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 structures are HER dimerization inhibitors. It is unpredictable to determine ligand dependent and ligand independent HER dimerization inhibitors based on the HER2 binding site. Further, a structure activity relationship is unknown in the prior art regarding what antibody structures target subdomain II of an extracellular domain of HER2 protein.
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 (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) 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).
3) Low HER2 expressing tumors have been previously identified to be sensitive to HER2 targeted ADCs. Doi T et al. (Lancet Oncol 2017; 18: 1512–22, IDS reference) taught trastuzumab deruxtecan showed antitumor activity in HER2-low breast and gastric tumors (page 1513, Research in context box, Implications of all the available evidence). Doi taught low HER2-expressing tumors were defined as IHC1+/FISH negative, IHC1+/FISH untested, or IHC2+/FISH negative (page 1518, right column, last sentence), which were tested clinically. Doi taught two responders were IHC1+ or IHC2+/FISH negative (page 1518, right column last paragraph). While Doi further taught that there is precedence for treatment of HER2 targeting agents with low or even negative HER2 IHC expression (page 1513, left column, second to last paragraph), these examples express higher than normal serum concentrations of HER2 extracellular domain and thus are still targeted toward HER2. Thus, the expectation that patients with tumors that do not possess qualities wherein the serum concentrations of HER2 extracellular domain is elevated would not be expected to be targeted by HER2 without HER2 expression.
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 claimed by function in claims 1-7, 10-11, 26-32, 35-36, 38-50. A structure activity relationship is not disclosed for what inhibitors can or cannot inhibit HER dimerization Pertuzumab was the only HER dimerization inhibitor tested;
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 8 and 33. 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; and
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 1-10, 26-35, 38-42, 48, and 50 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).
Regarding instant claims 1-10, 26-35, 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 1-10, 26-35, 38-42, 48, and 50.
Claims 1-4, 6-7, 11, 26-29, 31-32, 36, 38-40, 44, 48 and 50 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US 20160333112 (Naito H et al.) and evidenced by Junttila TT et al. (Cancer Cell 2009 15 (5) 429-440), ADC Review (https://www.adcreview.com/trastuzumab-deruxtecan-drug-description/), and SciFinder Trastuzumab deruxtecan (CAS RN 1826843-81-5 retrieved 2025).
Regarding claims 1-4, 6-7, 11, 26-29, 31-32, 36, 38-40 Naito taught a method of treating breast cancer (instant claims 38-40) that expressed HER2 in a subject comprising administering a pharmaceutical composition of the anti-HER2 trastuzumab linked exatecan ADC of example 50 (instant claims 1-4, 6-7, 11, 26-29, 31-32, 36) was more effective than trastuzumab at inhibiting HER2 expressing breast tumor growth in vivo (Fig. 8 and 9). Junttila evidenced that the antibody trastuzumab inhibits the ligand-independent HER2/HER3 Interaction (Junttila, Fig. 3); thus the ADC of example 50, which is comprised of trastuzumab and a drug conjugate, is also a HER2 dimerization inhibitor.
Regarding claims 41-43 and 46, Naito taught a method of cancer treatment wherein a subject with cancer was administered a pharmaceutical composition comprising the anti-HER2 trastuzumab linked exatecan ADC of example 50 and 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, 48 and 50, 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 (instant claim 44), while trastuzumab and a different ADC of trastuzumab linked emtansine were not effective (pages 102-103, paragraph 767-769 and Fig.9). This method would naturally exert a significantly superior antitumor effect than administration of a single molecule of the anti-HER2 antibody-drug conjugate and a naturally exert synergistic antitumor effect (instant claims 48 and 50).
Regarding the structure and sequence of the ADC, 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). 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 2-4 and 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); or 2) 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.
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 1-11, 26-36, and 38-50 are rejected under 35 U.S.C. 103 as being unpatentable over US 20160333112 (Naito H et al.) 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/) and SciFinder Trastuzumab deruxtecan (CAS RN 1826843-81-5 retrieved 2025).
Regarding claims 1-11, 26-36, and 38-50, 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 1-11, 26-36, and 38-50, 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 1-11, 26-36, and 38-50, 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 1-11, 26-36, and 38-50, 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 1-11, 26-36, and 38-44, 46, 48-50, 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 claims 10 and 35) administering a pharmaceutical composition of the anti-HER2 ADC (instant claims 2-3) linked exatecan of Naito example 50 and the extracellular domain II targeting HER2 heterodimer antibody inhibitor pertuzumab (instant claims 8-9 and 33-34) 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, and 32); 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 treat; 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 (instant claims 48 and 50).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
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Claims 1-7, 10, 26-32, 35, 38-40, 48, and 50 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-62 and 125-130 of copending Application No. 17/416,487 in view of Feldinger K et al. (Breast Cancer: Targets and Therapy 2015:7 147–162).
Copending claims 1-62 and 125-130 of ‘487 taught methods of treating cancer in a subject, comprising administering an antibody-drug conjugate and administering a kinase inhibitor in combination to a subject with cancer, wherein the antibody-drug conjugate is conjugated to a drug-linker represented by the following formula
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Regarding the kinase inhibitor, copending claims 29-30 taught the kinase inhibitor is a HER2 inhibitor, wherein the HER2 inhibitor is tucatinib, neratinib, mubritinib, lapatinib, pyrotinib, or poziotinib, or a pharmacologically acceptable salt thereof.
Regarding the antibody, copending claims 32-37 taught the antibody as a HER2 antibody, wherein: 1) copending claim 35, taught the anti-HER2 comprised a heavy chain consisting of SEQ ID NO: 1 and a light chain consisting of SEQ ID NO: 2; 2) copending claim 36 taught the anti-HER2 comprised a heavy chain consisting of amino acid residues 1 to 449 of SEQ ID NO: 1 and a light chain consisting of amino acid residues 1 to 214 of SEQ ID NO: 2; and copending claim 33 and 34 taught variable heavy and variable light chain sequences and their CDRs of SEQ ID NO: 1 and SEQ ID NO: 2.
Regarding the number of drug linkers, copending claims 37 and 127, taught the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is from 7 to 8. The subject matter of copending claim 127 produces an ADC of trastuzumab deruxtecan.
Regarding cancer treatment, copending claim 56 taught the treatment of breast cancer.
While the claims of copending ‘487 taught a method of treating cancer wherein the HER2 ADC is administered in combination with the kinase inhibitor neratinib, which is a HER2 dimerization inhibitor among several embodiments, this embodiment is further obvious and supported in view of Feldinger.
Feldinger taught neratinib was able to suppress ligand-stimulated HER2–HER3 dimers and could effectively disrupt preformed HER2–HER3 dimers (page 150, right column, second paragraph). Feldinger taught neratinib has been shown to be effective against HER2-overexpressing or mutant tumors in vitro and in vivo (abstract). Feldinger taught neratinib is an oral tyrosine kinase inhibitor (TKI). Feldinger taught trastuzumab and neratinib treatment in combination was more effective than either treatment alone in vivo (page 150, right column, second paragraph).
Regarding instant claims it would have been obvious for a person having ordinary skill in the art to take the method of copending claims 1, 2, 30, 35-37, 56, and 127 for a method of treating breast cancer in a subject, comprising administering an antibody-drug conjugate and administering a kinase inhibitor in combination to a subject with breast cancer, wherein the antibody-drug conjugate is conjugated to a drug-linker of
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,
wherein the kinase inhibitor is the HER2 inhibitor is neratinib,
wherein the antibody is an anti-HER2 antibody of: a) a heavy chain consisting of SEQ ID NO: 1 and a light chain consisting of SEQ ID NO: 2; or b) a heavy chain consisting of amino acid residues 1 to 449 of SEQ ID NO: 1 and a light chain consisting of amino acid residues 1 to 214 of SEQ ID NO: 2,
wherein the number of drug linkers in the antibody-drug conjugate is from 7 to 8,
wherein the ADC is trastuzumab deruxtecan – and:
Use the oral TKI neratinib as an effective treatment of HER2 overexpressing cancers and an inhibitor of HER2 dimerization.
This is obvious because: 1) Feldinger taught neratinib was able to suppress ligand-stimulated HER2–HER3 dimers and could effectively disrupt preformed HER2–HER3 dimers and Feldinger taught neratinib as an effective treatment of HER2 overexpressing cancers, wherein trastuzumab and neratinib treatment in combination was more effective than either treatment alone in vivo.
There is a reasonable expectation of success because: 1) Feldinger taught neratinib was able to suppress ligand-stimulated HER2–HER3 dimers and could effectively disrupt preformed HER2–HER3 dimers and Feldinger taught neratinib as an effective treatment of HER2 overexpressing cancers, wherein trastuzumab and neratinib treatment in combination was more effective than either treatment alone in vivo. Thus, the combination treatment would be effective.
This meets the claim limitations of instant claims 1-7, 10, 26-32, 35, 38-40. 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 is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowable.
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/J.J.S./Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643