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 .
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 03/08/2024 is in compliance with the provisions of 37 CFR 1.97. She (Source #136) and Veryhoeyan (Source #152) were not placed in the application contents and have been lined through.
Accordingly, the information disclosure is being considered by the examiner, except where lined through.
Specification
The disclosure is objected to because of the following informalities: The specification teaches SEQ ID NO: 7 which is a skipped sequence. Applicant is required to replace SEQ ID NO: 7 with “WAS” in the specification.
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 25, 26, 31, 36, 38, 39, and 45 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 25 and 26 are rejected as indefinite because it is unclear if a) “IHC 2+/fluorescence in situ hybridization (FISH) negative” requires either IHC2+ or FISH negative detection or b) if a HER2-low expressing breast cancer diagnosis requires both IHC2+ and FISH negative results. For the purposes of claim interpretation and in alignment with the prior art, “IHC2+/fluorescence in situ hybridization (FISH) negative” with be interpreted as both an IHC2+ and a FISH negative result are required in order for a patient to be considered HER2-low expressing.
Claim 31 is rejected as indefinite because SEQ ID NO: 7 corresponds to an amino acid sequence that is skipped sequence. According to Claim 31, SEQ ID NO: 7 is supposed to be referencing “WAS”. “WAS” is three amino acids and does not meet the minimum requirement for a sequence to be part of the sequence listing under ST26. Applicant is required to amend the claim to remove “SEQ ID NO: 7”.
Claim 36 is rejected as indefinite because it is unclear if “is shown in” is limiting (i.e. consists of) to the recited SEQ ID NO.. Therefore, the metes and bounds of what heavy and light chains read on the limitation is unclear. For the purposes of examination “is shown in” will be interpreted as “comprises”. Examiner recommends amending to: “…the heavy chain comprises…the light chain comprises…”
Claim 38 recites the limitation of “the average Drug-to-Antibody Ratio (DAR) value” in line 1. There is insufficient antecedent basis for this limitation in the claim. For the purposes of examination, it will be interpreted as “the ADC comprises an average Drug-to-Antibody Ratio”. Claim 39 is included in this rejection because it is dependent from claim 38.
Claim 45 recites the limitation "the medicine" in line 1. There is insufficient antecedent basis for this limitation in the claim. For the purposes of examination, it will be interpreted as “the antibody-drug conjugate”.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 28 and 35 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 28 fails to further limit the claim from which it depends, Claim 24. Claim 24 recites that the complementary determining regions (CDRs) of the anti-HER2 antibody are the same as Disitamab vedotin, which is a humanized antibody with mouse CDRs; however, claim 28 broadens the scope of claim 24 by reciting that the anti-HER2 antibody is murine, chimeric, humanized or fully human. Because the CDRs of Disitamab vedotin are derived from a mouse, the antibody of claim 28 cannot be fully human.
Claim 35 fails to further limit the claim from which it depends because it recites all of the IgG isotypes encompassed by claim 34.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 24-30, 34-35, 38-46 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the 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.
The claimed invention:
Claim 24 and its dependents 25-30, 34-35, and 38-46 recite a method of treating HER2-low expressing breast cancer by administering an antibody drug conjugate (ADC) comprising an antibody capable of binding HER2 comprising CDR sequences of the heavy or light chain variable region that have the same sequences as Disitamab vedotin.
Accordingly, the claim encompasses a genus of ADCs comprising the partial structure of HER2 antibodies with either the VH CDRs of Disitamab vedotin or the VL CDRs of Disitmab vedotin that function to bind HER2 to treat HER2-low expressing breast cancer.
State of the Prior Art:
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) that provide the majority of the contact residues for the binding of the antibody to its target epitope (Almagro, Progress and Challenges in the Design and Clinical Development of Antibodies for Cancer Therapy Frontiers in Immunology, 2018; specifically, page 3, “The IgG Molecule”; Figure 1; see instant PTO-892).
It was also well known in the art that small changes within the CDR region of antibodies could drastically impact antibody function. For example, Hall (The Journal of Immunology, 1992, abstract; see instant PTO-892) teaches that a single amino acid change in the CDR3 of the VL chain abolished antibody binding activity. Furthermore, while affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody, those techniques involve trial-and-error testing and the changes that maintain or improve affinity are unpredictable to those of ordinary skill in the art (Almagro, pages 3 and 6-7).
Although advances in computational modelling of CDRs around the time of filing led to improvements in rational mutagenesis of antibodies, the overall effects of any given mutation on antibody function remain unpredictable. For example, Chiu et al. 2019 (Antibodies, 8(4), 55.; see instant PTO-892) teaches that although modeling has proven accurate for framework region sequences, CDR modeling requires further development and improvement (Pg. 6, ¶2). Even after the filing date, Svilenov (Approaches to expand the conventional toolbox for discovery and selection of antibodies with drug-like physicochemical properties, 2023, mAbs, pg. 11, left side, second paragraph; see instant PTO-892) in silico tools alone were not sufficient for antibody design: “The de novo design of antibody binding using approaches relying on molecular modelling has generally met low success rates and required recursive experimental screenings and large libraries…” and that predicting the combined effects of multiple mutations was difficult (pg. 5, left side, second paragraph).
Altogether, these sources teach that variation, particularly within the CDR sequences, can directly impact an antibody’s ability to bind to its target, but one of ordinary skill in the art would not be able to predict which changes would do so.
Regarding HER2 antibodies specifically comprising the Disitamab vedotin CDR sequences that function to treat cancer, the state of the art teaches a few species, but all
contained both the heavy and light chain CDR sequences of Disitamab vedotin. For example, Gardai SEQ ID NOs: 99 and 100 of US20230270877A1 teaches different sequences from SEQ ID NOs: 236 and 237 of Ray WO2021087245A1, but both comprise the same CDR sequences.
Altogether, the state of the art teaches the unpredictability of antibody function based on partial structure of Disitamab vedotin CDRs. Based on the techniques and the state of the art at the time of filing, one of ordinary skill in the art would not be able to envisage the species of HER2 antibodies with heavy or light chain CDR sequences of Disitamab vedotin within the claimed genus that can execute the claimed function of binding HER2 to treat HER2-low expressing breast cancer.
Description of representative species in the specification:
If the state of the art does not constitute the recited genus, possession can be demonstrated through a representative number of species described in the specification.
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
However, the only ADC disclosed in the specification (pg. 24, [0087], [0088]) is Disitamab vedotin, which can comprise the CDR combinations described in Table 2 (pg. 13 of the specification) according to IMGT numbering or Table 3 (pg. 13 of the specification) according to Kabat numbering.
Thus, this single embodiment is not enough to constitute the genus of anti-HER2 antibodies in an ADC composition that have either the VL or VH CDRs of Disitamab vedotin that function to bind to HER2 to treat HER2-low expressing breast cancer.
Relationship between Structure and Function:
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied by 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. However, in the instant case, there is no way to a priori look at an antigen sequence and envision the combination of six CDRs that will bind that antigen. In the genus recited, up to three CDRs of the claimed HER2 antibody could be novel.
There is no discussion in the specification that addresses what structural components (i.e. amino acid resides) must be preserved in order to maintain binding functionality of the antibody to HER2. The specification does not address the evidence in the art that a single point mutation in just one CDR region can ablate binding capability. Thus, given the lack of well-established correlation between structure and function, written description is not satisfied through recitation of function (i.e. binding to HER2 to treat HER2-low breast cancer) and minimal structure (i.e. heavy or light chain CDRs of Disitamab vedotin).
Based on the disclosure, one of ordinary skill would not immediately envisage which species of HER2 antibodies, especially those comprising variation in the binding regions, maintain functional binding.
Conclusion:
Given the state of the art, and the limited breadth and number of species relative to the claimed genus, as well as the lack of necessary structural features to achieve the claimed function, one of ordinary skill in the art would not be able to immediately envisage possession of the genus of ADCs comprising antibodies which bind to HER2 comprising partial structure of Disitamb vedotin.
Claim 45 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for intravenous, subcutaneous, intradermal, and intramuscular administration of an ADC comprising a HER2 antibody, mc-vc-pAB linker, and MMAE, does not reasonably provide enablement for administration intranasally. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
MPEP § 2164.01(a) states that there are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue”. These factors include, but are not limited to:
A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01.
Breadth of the claim:
Claim 45 recites that the antibody drug conjugate (ADC) comprising an anti-HER2 antibody, the cleavable linker mc-vc-pAB, and the cytotoxic molecule MMAE can be administered subcutaneously, intradermally, intramuscularly, intravenously, or intranasally to treat HER2-low expressing breast cancer. Accordingly, there are a wide variety of administration methods claimed but the specification is not enabling for intranasal administration.
State of the Prior Art:
At the time of filing, all FDA approved antibody drug conjugates were only administered intravenously or through intravenous infusion. Alves (Antibody conjugation and formulation, 2019, Antibody Therapeutics pgs. 33-39; see instant PTO-892) teaches intramuscular and subcutaneous routes of administration were being explored because of their enhanced accessibility (abstract). Furthermore, the teachings of Jung (Effect of berahyaluronidase alfa on subcutaneous absorption and local tolerability of ALT-P7, an antibody-drug conjugate in preclinical studies, 2026, Journal of Controlled Release; see instant PTO-892) of a HER2 antibody drug conjugate administered intradermally, intravenously, and subcutaneously suggests that successful formulation administration of the instant HER2 ADC would not have been undue experimentation at the time of filing.
However, regarding intranasal delivery, Ozsoy (Nasal Delivery of High Molecular Weight Drugs, 2009, Molecules, pgs. 3754–3779; see instant PTO-892) teaches that compositions with high molecular weight (roughly 1,000 Daltons) struggle to pass through the nasal epithelia barrier and that enzymes present in the nasal mucosa can break down protein macromolecules (pg.3772, Conclusions, first 10 lines). In the instant case, the ADC claimed can comprise up to eight monomethyl auristatin E (MMAE) cytotoxic molecules; as taught by ADC Review (What is Monomethyl Auristatin E (MMAE)?, 2019, pg. 1; see instant PTO-892) each MMAE molecule is roughly 718 Daltons (pg. 1, “Molecular Weight”). Therefore, the cytotoxic drug load of the claimed ADC alone would well exceed the molecular weight limit able to pass through nasal epithelia barrier.
Altogether, these sources teach that the state of the art is not enabling for administration of an ADC for the treatment of a condition via intranasal administration.
Amount of direction provided by the inventor and existence of working examples:
The example in the specification (pgs. 24-29) does not specify the method of administration. Therefore, there is no support in the specification for intranasal administration. There is no direction provided in the specification to address the concerns about barriers due to size or enzyme breakdown via intranasal administration stated in the prior art.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure:
The state of the art teaches that those skilled in the art are attempting to create more accessible methods of administration for ADCs but limited if any art exists regarding successful intranasal administration. Therefore, achieving successful intranasal ADC administration would itself be its own contribution to the field.
Given the lack of direction and working examples directed toward intranasal administration of the claimed ADC, coupled with the unpredictability in the art, it would take a substantial quantity of experimentation to successfully make and use the claimed invention.
Conclusion:
Therefore, there would not be a reasonable expectation of success without undue experimentation to administer a HER-2 ADC comprising a HER2 antibody, an mc-vc-pAB linker, and MMAE molecules, intranasally in order to treat HER-low expressing breast cancer. Therefore, the specification is only enabling for administering the claimed ADC subcutaneously, intradermally, intramuscularly or intravenously.
Claim Rejections - 35 USC § 103
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.
Claim(s) 24, 28-39 is/are rejected under 35 U.S.C. 103 as being unpatentable over Jiang (Preclinical safety profile of disitamab vedotin:a novel anti-HER2 antibody conjugated with MMAE, 2019, Toxicology Letters, pgs. 30-37; instant IDS) in view of Behrens (Methods for site-specific drug conjugation to antibodies, 2014, Landes Bioscience, pgs. 46-53; see instant PTO-892), in further view of Xu (Abstract PD4-06: Early clinical development of RC48-ADC in patients with HER2 positive metastatic breast cancer, 2020, Cancer Res. Pgs. 1-2; see instant PTO-892) as evidenced by Precision FDA ( “Disitamab Vedotin”, 2026, Precision FDA, pgs. 1-11; see instant PTO-892) and Gardai US20230270877A1, effectively filed November 8th 2020, (see instant PTO-892).
Regarding Claims 24, 28, and 37 Jiang teaches an antibody-drug conjugate (ADC) Disitamab vedotin comprising Disitamab, a humanized monoclonal antibody targeting HER2, covalently attached by a cleavable linker to the cytotoxic molecule monomethyl auristatin E (MMAE) (pg. 31, left side, middle of first paragraph). Regarding claims 31, 32, 33, and 36 as evidenced by Gardai, the heavy chain of Disitamab vedotin is identical to instant SEQ ID NO: 1 and comprises instant SEQ ID NOs: 3-5, 9, and 11-13; furthermore, the light chain of Disitamab vedotin is identical to instant SEQ ID NO: 2 and comprises instant SEQ ID NOs: 6-8, 10, and 14-16 (see below and pg. 72 of Gardai). Regarding claims 29, 30, 34, and 35 as evidenced by Precision FDA, Disitamab vedotin is an IgG1 isotype. Regarding claims 38-39, Jiang teaches Disitamab vedotin has a DAR of 4 (pg. 31, second paragraph), which means an average of four cytotoxic molecules are bound to each antibody by the linker (pg. 31, left side, bottom half of first paragraph). Therefore, Disitamab vedotin necessarily has the general formula Ab-(L-U)n. Jiang teaches administration of Disitamab vedotin to monkeys and rats and that it was non-toxic in preclinical studies (pg. 35, left side, fourth paragraph).
Jiang does not explicitly teach that the linker comprises Maleimido-Caproyl-Valine-Citrulline-p-Aminobenzyloxy (mc-vc-pAB) which covalently links by sulfhydryl conjugation or that the linking site is the interchain disulfide bond site of the anti-HER2 antibody. Jiang does not explicitly teach that Disitamab Vedotin is administered in an effective amount to treat patients with HER2- low expressing breast cancer.
Behrens teaches Brentuximab vedotin is an FDA approved ADC in which a monoclonal antibody is conjugated to MMAE with the linker mc-vc-pAB (pg. 46, right side, last paragraph; pg. 47, Figure 1). Regarding claim 24, Behrens teachings that the linking site is the interchain disulfide bond of the antibody (Fig.1, Fig. 1 caption, and pg. 47). Behrens teaches that most human IgG molecules could accommodate up to eight drugs because the degree of conjugation is dependent on the extent of disulfide reduction; this level of conjugation has increased site control compared to another FDA approved ADC, which attaches a cytotoxic drug on up to 40 lysine residues (Fig. 1 Caption; pgs. 47-48). Behrens teaches that the optimal loading is 2 to 4 drugs per antibody (pg. 48, left side, bottom third of first paragraph). Furthermore, high loading can lead rapid clearance from circulation (pg. 48, left side, bottom third of first paragraph).
Xu teaches RC48-ADC is administered in an effective amount to treat HER2-low expressing breast cancer patients (pg. 2, Conclusion, last three lines). As evidenced by Precision FDA, RC48-ADC is the same as Disitamab Vedotin.
It would be obvious to substitute the cleavable linker in Disitamab vedotin taught by Jiang, with mc-vc-pAB taught by Behrens in order to arrive at an ADC comprising i) an anti-HER2 antibody comprising heavy and light chains of Disitamab vedotin (i.e. instant SEQ ID NOs: 1, and 2, which comprise SEQ ID NOs: 3-16), ii) a cleavable linker mc-vc-pAB, iii) a DAR of four MMAE molecules conjugated to the antibody via the linker at disulfide bond sites via sulfhydryl conjugation (hereafter “modified Disitamab vedotin”). One of ordinary skill in the art would be motivated to modify the Disitamab vedotin of Jiang with mc-vc-pAB of Behrens to arrive at modified Disitamab vedotin because it limits the DAR to eight drugs per antibody, keeping the DAR around the optimal range suggested by Behrens while avoiding high drug loading. There would be a reasonable expectation of success substituting the cleavable linker in Disitamab vedotin of Jiang because the mc-vc-pAB cleavable linker was FDA approved and a well-known ADC linker in the art.
Furthermore, it would be obvious to administer an effective amount of modified Disitamab vedotin of Jiang and Behrens to treat patients expressing HER2-low expressing breast cancer, as taught by Xu. One of ordinary skill in the art would be motivated to use the modified Disitamab vedotin composition of Jiang and Behrens to treat HER2-low expressing breast cancer based on the successful preliminary results of Disitamab vedotin taught by Xu. There would also be a reasonable expectation of success administering modified Disitamab vedotin to treat HER2-low expressing patients because of the successful preclinical results taught by Jiang and the successful results treating the HER2-low patient population of Xu; in other words, because modified Disitamab vedotin is identical to Disitamab vedotin, which had successful results in HER2 low-expressing patients, except for the substitution of a functionally equivalent linker, there would be a reasonable expectation of success treating HER2-low expressing patients with the modified Disitamab vedotin.
SEQ ID NO: 100 of Gardai Identical to instant SEQ ID NO: 2:
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SEQ ID NO: 99 of Gardai Identical to Instant SEQ ID NO: 1:
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Claim(s) 25-27 is/are rejected under 35 U.S.C. 103 as being unpatentable over Jiang (Preclinical safety profile of disitamab vedotin:a novel anti-HER2 antibody conjugated with MMAE, 2019, Toxicology Letters, pgs. 30-37; instant IDS), in view of Behrens (Methods for site-specific drug conjugation to antibodies, 2014, Landes Bioscience, pgs. 46-53; see instant PTO-892), in further view of Xu (Abstract PD4-06: Early clinical development of RC48-ADC in patients with HER2 positive metastatic breast cancer, 2020, Cancer Res. Pgs. 1-2; see instant PTO-892), as applied to claim 24 above, and as evidenced by Precision FDA, Gardai (US20230270877A1, effectively filed November 8th 2020; see instant PTO-892) and Study Details _ NCT03052634 (“A Study of RC48-ADC in Subjects With Advanced Breast Cancer” ClinicalTrials.gov, 2016; see instant PTO-892).
The modified method of Jiang, Behrens, and Xu, as evidenced by Precision FDA and Gardai, teach administration of modified Disitamab vedotin, which is an ADC comprising i) an anti-HER2 antibody comprising heavy and light chains of Disitamab vedotin (i.e. instant SEQ ID NOs: 1, and 2, which comprise SEQ ID NOs: 3-16), ii) a cleavable linker mc-vc-pAB, iii) a DAR of four MMAE molecules conjugated to the antibody via the linker at disulfide bond sites via sulfhydryl conjugation (hereafter “modified Disitamab vedotin”), in an effective amount to treat HER2-low expressing breast cancer.
The modified method of Jiang, Behrens, and Xu does not teach that a HER2-low expressing patient is a patient whose HER2 is detected as a) IHC1+ or b) IHC2+ and FISH negative in a sample from breast cancer.
Regarding claims 25-27, as evidenced by “Study Details _ NCT03052634”, the HER2-low expressing patients treated in Xu were determined by HER2 immunohistochemistry 2+ with FISH negative or HER2 immunohistochemistry 1+ (FISH negative or untested) by tumor site specimens (pg. 5, middle of page, “Explorative cohort”).
It would be obvious to modify the modified method of treating HER2-low expressing breast cancer patients of modified Jiang, Behrens, and Xu by specifically treating patients who are a) IHC1+ or b) IHC2+ and FISH negative, as taught by Xu , as evidenced by “Study Details _ NCT03052634” in order to arrive at a method of treating HER2-low expressing breast cancer patients identified by a) IHC1+ or b) IHC2+ and FISH negative result by administering an effective amount of modified Disitamab vedotin which comprises i) an anti-HER2 antibody comprising heavy and light chains of Disitamab vedotin (i.e. instant SEQ ID NOs: 1, and 2, which comprise SEQ ID NOs: 3-16), ii) a cleavable linker mc-vc-pAB, iii) a DAR of four MMAE molecules conjugated to the antibody via the linker at disulfide bond sites via sulfhydryl conjugation. One of ordinary skill in the art would be motivated to apply the modified method for treating HER2-low expressing breast cancer patients of Jiang, Behrens, and Xu to patients established as a) IHC1+ or b) IHC2+ and FISH negative because this is standard criteria for identifying the HER2-low breast cancer (BC) patient population. There would be a reasonable expectation of success treating HER2 low expressing patients, as identified through the standard criteria of a) IHC1+ or b) IHC2+ and FISH negative, by administration of modified Disitamab vedotin because of the successful results taught by Xu.
Claim(s) 40 is/are rejected under 35 U.S.C. 103 as being unpatentable over Jiang (Preclinical safety profile of disitamab vedotin:a novel anti-HER2 antibody conjugated with MMAE, 2019, Toxicology Letters, pgs. 30-37; instant IDS) in view of Behrens (Methods for site-specific drug conjugation to antibodies, 2014, Landes Bioscience, pgs. 46-53; see instant PTO-892), in further view of Xu (Abstract PD4-06: Early clinical development of RC48-ADC in patients with HER2 positive metastatic breast cancer, 2020, Cancer Res. Pgs. 1-2; see instant PTO-892), as applied to claim 24 above, and further in view of Lee, ( The histological diagnosis of metastases to the breast from extramammary malignancies, 2007, Journal of Clinical Pathology, pgs. 1333-1341; see instant PTO-892), as evidenced by Precision FDA ( “Disitamab Vedotin”, 2026, Precision FDA, pgs. 1-11; see instant PTO-892) and Gardai US20230270877A1, effectively filed November 8th 2020, (see instant PTO-892).
The modified method of Jiang, Behrens, and Xu, as evidenced by Precision FDA and Gardai, teach administration of modified Disitamab vedotin, which is an ADC comprising i) an anti-HER2 antibody comprising heavy and light chains of Disitamab vedotin (i.e. instant SEQ ID NOs: 1, and 2, which comprise SEQ ID NOs: 3-16), ii) a cleavable linker mc-vc-pAB, iii) a DAR of four MMAE molecules conjugated to the antibody via the linker at disulfide bond sites via sulfhydryl conjugation (hereafter “modified Disitamab vedotin”), in an effective amount to treat HER2-low expressing breast cancer.
The modified method of Jiang, Behrens, and Xu does not teach that breast cancer is metastatic breast cancer, which is established by histology, and is unresectable.
Xu teaches the ADC Disitamab vedotin is administered in an effective amount to treat HER2-low expressing breast cancer patients (pg. 2, Conclusion). Xu further teaches that the breast cancer treated with Disitamab vedotin is metastatic breast cancer (MBC) and the majority of patients had visceral metastasis (pg. 1, “Results”, lines 4-6).
Lee further teaches that histological features are used for the diagnosis of metastases to the breast (abstract).
It would be obvious to combine the HER2-low expressing breast cancer treatment of modified of Jiang, Behrens, and Xu with a method of identifying metastatic breast cancer by histology, as taught by Lee, to arrive at a method of treating a patient with unresectable HER2-low expressing MBC that is established by histology by administering an effective amount of modified Disitamab vedotin which comprises i) an anti-HER2 antibody comprising heavy and light chains of Disitamab vedotin (i.e. instant SEQ ID NOs: 1, and 2, which comprise SEQ ID NOs: 3-16), ii) a cleavable linker mc-vc-pAB, iii) a DAR of four MMAE molecules conjugated to the antibody via the linker at disulfide bond sites via sulfhydryl conjugation. One of ordinary skill in the art would have been motivated to combine the teachings of Jiang, Behrens, Xu, and Lee because Xu specifically teaches Disitamab vedotin is used to treat patients with MBC while Lee teaches how to identify MBC. While the visceral metastasis of MBC taught by Xu does not categorically mean the patients’ cancer was unresectable, one of ordinary skill in the art would recognize that the patient population with unresectable MBC greatly overlaps with the patient population of visceral metastasis of MBC because when the cancer spread is extensive or to certain regions it becomes unresectable; thus, it would be obvious for one of ordinary skill to arrive at the claimed invention of treating unresectable MBC based on the teachings of visceral metastasis by Xu. There would be a reasonable expectation of success combining a method of treating a patient population, namely the modified method of Jiang, Behrens, and Xu treating HER2-low expressing MBC patients, with a method of identifying said patient population, namely using histological features of MBC taught by Lee.
Claim(s) 41-43 is/are rejected under 35 U.S.C. 103 as being unpatentable over Jiang (Preclinical safety profile of disitamab vedotin:a novel anti-HER2 antibody conjugated with MMAE, 2019, Toxicology Letters, pgs. 30-37; instant IDS) in view of Behrens (Methods for site-specific drug conjugation to antibodies, 2014, Landes Bioscience, pgs. 46-53; see instant PTO-892), in further view of Xu (Abstract PD4-06: Early clinical development of RC48-ADC in patients with HER2 positive metastatic breast cancer, 2020, Cancer Res. Pgs. 1-2; see instant PTO-892), as applied to claim 24 above, and further in view of Ghersi (A systematic review of taxane-containing regimens for metastatic breast cancer, 2005, British Journal of Cancer, pgs. 291-301; see intrant PTO-892), as evidenced by Precision FDA ( “Disitamab Vedotin”, 2026, Precision FDA, pgs. 1-11; see instant PTO-892) and Gardai US20230270877A1, effectively filed November 8th 2020, (see instant PTO-892).
The modified method of Jiang, Behrens, and Xu, as evidenced by Precision FDA and Gardai, teach administration of modified Disitamab vedotin, which is an ADC comprising i) an anti-HER2 antibody comprising heavy and light chains of Disitamab vedotin (i.e. instant SEQ ID NOs: 1, and 2, which comprise SEQ ID NOs: 3-16), ii) a cleavable linker mc-vc-pAB, iii) a DAR of four MMAE molecules conjugated to the antibody via the linker at disulfide bond sites via sulfhydryl conjugation (hereafter “modified Disitamab vedotin”), in an effective amount to treat HER2-low expressing breast cancer.
The modified method of Jiang, Behrens, and Xu does not teach that the patient had previously received one or more treatments. It also does not teach that the previous treatment was chemotherapy. It also does not teach that the patient had previously received taxane systemic therapy.
Regarding claims 41 and 42, Xu further teaches that most patients had also received at least two treatments of chemotherapy (pg. 1, “Results”, lines 4-6).
Regarding claim 43, Ghersi teaches taxane-containing chemotherapy was successful in women with MBC (abstract). Ghersi teaches that this treatment was more effective than some nontaxane treatment regimens (pg. 299, left side, second paragraph, last four lines).
It would be obvious to modify the HER2-low expressing breast cancer treatment of modified of Jiang, Behrens, and Xu by pre-treating the patient with taxane-containing chemotherapy at least once in order to arrive at a method of treating HER2-low expressing breast cancer by a) pretreating the patient with a taxane-containing chemotherapy at least once and b) administering an effective amount of modified Disitamab vedotin which comprises i) an anti-HER2 antibody comprising heavy and light chains of Disitamab vedotin (i.e. instant SEQ ID NOs: 1, and 2, which comprise SEQ ID NOs: 3-16), ii) a cleavable linker mc-vc-pAB, iii) a DAR of four MMAE molecules conjugated to the antibody via the linker at disulfide bond sites via sulfhydryl conjugation. One of ordinary skill in the art would be motivated to combine the teachings of Jiang, Behrens, Xu and Ghersi because Xu specifically teaches that the majority of patients receiving Disitamab vedotin had already received two treatments of chemotherapy. There would be a reasonable expectation of success treating HER2-low expressing breast cancer patients with taxane-containing chemotherapy prior to treatment with the modified Disitamab vedotin of Jiang, Behrens, and Xu because taxane chemotherapy is more effective in comparison to non-taxane containing regiments, as taught by Ghersi.
Claim(s) 44 is/are rejected under 35 U.S.C. 103 as being unpatentable over Jiang (Preclinical safety profile of disitamab vedotin:a novel anti-HER2 antibody conjugated with MMAE, 2019, Toxicology Letters, pgs. 30-37; instant IDS) in view of Behrens (Methods for site-specific drug conjugation to antibodies, 2014, Landes Bioscience, pgs. 46-53; see instant PTO-892) , in further view of Xu (Abstract PD4-06: Early clinical development of RC48-ADC in patients with HER2 positive metastatic breast cancer, 2020, Cancer Res. Pgs. 1-2; see instant PTO-892), as applied to claim 24 above, in further view of Tarantino (HER2-Low Breast Cancer: Pathological and Clinical Landscape, 2020, Journal of Clinical Oncology, pgs. 1951-1963; see instant PTO-892) as evidenced by Precision FDA ( “Disitamab Vedotin”, 2026, Precision FDA, pgs. 1-11; see instant PTO-892) and Gardai US20230270877A1, effectively filed November 8th 2020, (see instant PTO-892).
The modified method of Jiang, Behrens, and Xu, as evidenced by Precision FDA and Gardai, teach administration of modified Disitamab vedotin, which is an ADC comprising i) an anti-HER2 antibody comprising heavy and light chains of Disitamab vedotin (i.e. instant SEQ ID NOs: 1, and 2, which comprise SEQ ID NOs: 3-16), ii) a cleavable linker mc-vc-pAB, iii) a DAR of four MMAE molecules conjugated to the antibody via the linker at disulfide bond sites via sulfhydryl conjugation (hereafter “modified Disitamab vedotin”), in an effective amount to treat HER2-low expressing breast cancer.
The modified method of Jiang, Behrens, and Xu does not teach that the patient has previously received trastuzumab.
Regarding claim 44, Xu further teaches a majority of patients had been treated with trastuzumab prior to being treated with Disitamab vedotin.
Tarantino teaches trastuzumab as an adjuvant therapy to chemotherapy did not effectively treat HER2-low expressing breast cancer patients and teaches “limited clinical value of HER2-pathway blockade with trastuzumab” for HER2 low BC (pg. 1953, right side, last paragraph).
It would be obvious to combine the method of treating HER2-low expressing BC of modified of Jiang, Behrens, and Xu with the HER2-low expressing BC patient population that has been previously treated with trastuzumab of Tarantino to arrive at a method of treating HER-2 low expressing breast cancer patients who have previously received trastuzumab, by administering an ADC comprising i) an anti-HER2 antibody comprising heavy and light chains of Disitamab vedotin (i.e. instant SEQ ID NOs: 1, and 2, which comprise SEQ ID NOs: 3-16), ii) a cleavable linker mc-vc-pAB, iii) a DAR of four MMAE molecules conjugated to the antibody via the linker at disulfide bond sites via sulfhydryl conjugation. One of ordinary skill would be motivated to combine the modified method Jiang, Behrens, and Xu, with the HER-2 BC patient population previously treated with trastuzumab because 1) Xu teaches that the majority of patients treating the Disitamab vedotin ADC had been previously treated with trastuzumab, and 2) Tarantino teaches limited clinical value of trastuzumab for this patient population, meaning patients who had received trastuzumab likely still require treatment. There would be a reasonable expectation of success treating the HER2-low BC patient population that has received trastuzumab treatment with the modified method of Jiang, Behrens, and Xu teach because of the successful results taught by Xu.
Claim(s) 45 and 46 is/are rejected under 35 U.S.C. 103 as being unpatentable over Jiang (Preclinical safety profile of disitamab vedotin:a novel anti-HER2 antibody conjugated with MMAE, 2019, Toxicology Letters, pgs. 30-37; instant IDS) in view of Behrens (Methods for site-specific drug conjugation to antibodies, 2014, Landes Bioscience, pgs. 46-53; see instant PTO-892), in further view of Xu (Abstract PD4-06: Early clinical development of RC48-ADC in patients with HER2 positive metastatic breast cancer, 2020, Cancer Res. Pgs. 1-2; see instant PTO-892), as applied to claim 24 above, as evidenced by Precision FDA ( “Disitamab Vedotin”, 2026, Precision FDA, pgs. 1-11; see instant PTO-892) and Gardai US20230270877A1, effectively filed November 8th 2020, (see instant PTO-892).
The modified method of Jiang, Behrens, and Xu, as evidenced by Precision FDA and Gardai, teach administration of modified Disitamab vedotin, which is an ADC comprising i) an anti-HER2 antibody comprising heavy and light chains of Disitamab vedotin (i.e. instant SEQ ID NOs: 1, and 2, which comprise SEQ ID NOs: 3-16), ii) a cleavable linker mc-vc-pAB, iii) a DAR of four MMAE molecules conjugated to the antibody via the linker at disulfide bond sites via sulfhydryl conjugation (hereafter “modified Disitamab vedotin”), in an effective amount to treat HER2-low expressing breast cancer.
Regarding claim 45, Jiang further teaches that cynomolgus monkeys were administered Disitamab vedotin intravenously (pg. 31, left side, last paragraph). Furthermore, Jiang suggests cancer treatment in humans with a Disitamab vedotin dose of 2.0 mg/kg or 2.5 mg/kg (pg. 35, right side, second paragraph).
Regarding Claim 46, Xu teaches that low HER2-expression MCB patients had preliminary success with Disitamab vedotin at a 2.0 mg/kg dose once every two weeks (pg. 2, “Conclusion”, last three lines).
It would be obvious to modify the dosing regimen in the method of treating HER2-low expressing breast cancer of modified of Jiang, Behrens, and Xu with a 2.0mg/kg dose every two weeks intravenously to arrive at a method of treating HER2-low expressing BC by administering an effective amount of modified Disitamab vedotin which comprises i) an anti-HER2 antibody comprising heavy and light chains of Disitamab vedotin (i.e. instant SEQ ID NOs: 1, and 2, which comprise SEQ ID NOs: 3-16), ii) a cleavable linker mc-vc-pAB, iii) a DAR of four MMAE molecules conjugated to the antibody via the linker at disulfide bond sites via sulfhydryl conjugation to subjects intravenously at a 2.0 mg/kg dose every two weeks. One of ordinary skill in the art would have been motivated to administer the modified Disitamab vedotin composition at this dosing regimen because of a) successful preclinical results of a repeated intravenous dosing regimen of Disitamab vedotin in monkeys taught by Jiang and b) successful teaching of a 2.0mg/kg dose every two weeks of Disitamab vedotin for human patients taught by Xu. There would be a reasonable expectation of success treating HER2-low expressing breast cancer patients with the modified Disitamab vedotin of Jiang, Behrens, and Xu based on Xu ’s teachings that a 2.0mg/kg dose of Disitamab vedotin had successful results for this patient population.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Instant claims 24-46 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 9, 10, 11, 14-28 of U.S. Application No. 18450966 in view of Xu (Abstract PD4-06: Early clinical development of RC48-ADC in patients with HER2 positive metastatic breast cancer, 2020, Cancer Res. Pgs. 1-2; see instant PTO-892), as evidenced by Precision FDA ( “Disitamab Vedotin”, 2026, Precision FDA, pgs. 1-11; see instant PTO-892) and Study Details _ NCT03052634 (“A Study of RC48-ADC in Subjects With Advanced Breast Cancer” ClinicalTrials.gov, 2016; see instant PTO-892).
Regarding instant claims 24, 31, 32, 38 and 39, ‘966 copending claims 1-2, 7, 9-11,14-28 claim a method for treating a breast cancer patient with liver metastasis comprising administering an effective amount of ADC with the formula Ab-(L-U)n comprising i) an anti-Her2 antibody, ii) an mc-vc-pAB linker covalently linked to the antibody by means of sulfhydryl conjugation and the linking site is the interchain disulfide bond site of the antibody, iii) the cytotoxic molecule MMAE, iv) the CDR regions identical to the CDR sequences of instant claim 31 (instant SEQ ID NOs 3-8) or instant claim 32 (instant SEQ ID NOs 11-16), wherein the DAR value is 4 +/- 0.5. Regarding instant claim 28, claim 14 of ‘966 teaches that the antibody is humanized. Regarding instant claims 29, 30, 34 and 35, claims 17-18 of ‘966 teach that the antibody has an IgG1 isotype. Regarding instant claim 33, claim 15 of ‘966 recites identical heavy and light chains as instant SEQ ID NOs: 9 and 10. Regarding instant claim 36, claim 18 of ‘966 teaches that the antibody has identical heavy and light chains as instant SEQ ID NOs: 1 and 2. Regarding instant claim 37, claim 19 of ‘966 teaches that the ADC is Disitamab vedotin. Regarding instant claim 40, claim 11 of ‘966 teaches that the breast cancer is infiltrating locally advanced or MBC as established by cytology and is unresectable. Regarding instant claims 41-42, claims 22-23 of ’966 teach that the patient has had one or prior treatments of chemotherapy. Regarding instant claims 43-44, claims 23-24 of ‘966 teach that the patient has previously received trastuzumab. Regarding instant claim 45, claim 25 of ‘966 teaches that the ADC composition is administered intravenously. Regarding instant claim 46, claim 26 of ‘966 teaches that the ADC is administered at a dose of 2.0 mg/kg every two weeks.
‘966 does not teach a method of treating HER2-low expressing breast cancer, wherein HER2 is detected as a) IHC1+ or b) IHC2+ and FISH negative in a sample from breast cancer.
The teachings of Xu, as evidenced by Precision FDA and Study Details _ NCT03052634 are described above.
Regarding instant claims 24-46 it would have been obvious for a person having ordinary skill in the art to modify the method of treating breast cancer by administering an HER2 ADC in copending claims 1-2, 7-9 11,14-28 of ‘966 to treat the HER2-low expressing breast cancer patient population, wherein the patients have HER2 detected as IHC1+ or IHC 2+/FISH negative in a sample of breast cancer. This would produce a method of treating HER2-low expressing breast cancer with the same active method steps and patient population as instant claims 24-46. One of ordinary skill would be motivated to use the method of the reference application to treat the HER2-low expressing patient population because Xu teaches that RC48-ADC, a HER2 ADC comprising MMAE, was successful in treating HER2-low expressing patients; as evidenced by Study Details _ NCT03052634, the HER2-low patients of Xu were IHC1+ or IHC 2+/FISH negative. Xu’s successful results also demonstrate that there would a reasonable expectation of success modifying the reference application to treat HER2-low expressing patients, identified as IHC 2+/FISH negative.
Claims 24, 28-37, 40, 45 and 46 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-8, 12, 15, 16, 25, 36, 38, 42, 55, 57, 89, and 99 of 19/564737 in view of Behrens (Methods for site-specific drug conjugation to antibodies, 2014, Landes Bioscience, pgs. 46-53; see instant PTO-892), as evidenced by Precision FDA ( “Disitamab Vedotin”, 2026, Precision FDA, pgs. 1-11; see instant PTO-892).
Regarding instant claims 24, 32, Claims 1 and 25 of ‘737 teaches a method for treating cancer, wherein the cancer is breast cancer, in an individual by administering an effective amount of an anti-HER2 antibody comprising a VH domain comprising CDR sequences identical to instant SEQ ID NOS: 11-13 and a VL domain comprising CDR sequences identical to instant SEQ ID NOs: 14-16. Regarding instant claim 24, claims 6-8 teach that the cytotoxic molecule is MMAE. Regarding instant claim 24, claim 12 of ‘737 teaches that the ADC has a formula Ab-(L-U)n and has 1 to 8 cytotoxic molecules attached to the antibody. Regarding instant claims 31, 33, 36, claims 4 and 5 of ‘737 teach a VH domain SEQ ID NO: 10 and VL domain SEQ ID NO: 11 identical to instant VH and VL domains SEQ ID NOs: 1 and 2, respectively. Regarding instant claim 37, claim 15 of ‘737 teaches that the ADC is Disitamab vedotin. Regarding instant claims 28, 29, 30, 34, and 35, as evidenced by Precision FDA, Disitamab vedotin is a humanized antibody and has an IgG1 isotype. Regarding instant claim 45 and 46, claims 38 and 56 of ‘737 teach that the ADC is administered at a 2.0mg/kg dose every two weeks intravenously.
‘737 does not teach that the linker is an mc-vc-pAB wherein the linker covalently links the anti-HER2 antibody by means of sulfhydryl conjugation and the linking site is the interchain disulfide bond site.
The teachings of Behrens are above.
It would be obvious to modify the linker between the cytotoxic molecule and the anti-HER2 antibody of the ADC composition in the method of treating HER2-low expressing breast cancer of ‘737 with mc-vc-pAB of Behrens. This would produce an ADC composition comprising i) a humanized IgG1 anti-HER2 antibody with CDR sequences of Disitamab vedotin, ii) an mc-vc-pAB linker that attaches to the antibody up to eight times via sulfhydryl conjugation and the linking site is the interchain disulfide bond of the antibody, and iii) the cytotoxic molecule MMAE to arrive at a method of treating HER2-low expressing breast cancer with the same active method steps and patient population as the instant application. One of ordinary skill would be motivated to use the mc-vc-pAB linker because it limits the DAR to eight drugs per antibody, keeping the DAR around the optimal range suggested by Behrens while avoiding high drug loading. There would be a reasonable expectation of success substituting the linker of ‘737 because the mc-vc-pAB cleavable linker was FDA approved and a well-known ADC linker in the art.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 25-27 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-8, 12, 15, 16, 25, 36, 38, 40, 42, 55, 57, 89, and 99 of 19/564737 in view of Behrens (Methods for site-specific drug conjugation to antibodies, 2014, Landes Bioscience, pgs. 46-53), as applied to claim 24 above, in further view of Xu (Abstract PD4-06: Early clinical development of RC48-ADC in patients with HER2 positive metastatic breast cancer, 2020, Cancer Res. Pgs. 1-2), as evidenced by as evidenced by Precision FDA ( “Disitamab Vedotin”, 2026, Precision FDA, pgs. 1-11; see instant PTO-892) and Study Details _ NCT03052634 (“A Study of RC48-ADC in Subjects With Advanced Breast Cancer” ClinicalTrials.gov, 2016; see instant PTO-892).
The modified method of ‘737 and Behrens teaches a method of treating HER2-low expressing breast cancer patients by administering an ADC comprising i) an anti-HER2 antibody with CDR sequences of Disitamab vedotin, ii) an mc-vc-pAB linker that attaches to the antibody up to eight times via sulfhydryl conjugation and the linking site is the interchain disulfide bond of the antibody, iii) the cytotoxic molecule MMAE.
The modified method of Behrens and ‘737 does not teach that HER-low expressing patients are established by IHC1+ or IHC 2+/FISH negative.
The teachings of Xu are above, as evidenced by Study Details _ NCT03052634.
It would be obvious to modify the patient population in method of treating HER2-low expressing breast cancer patients of modified Behrens and ‘737 by detecting HER2-low patients via a IHC1+ or IHC2+/FISH negative result, as taught by Xu, to arrive at a method of treating HER2-low expressing breast cancer, identified as IHC1+ or IHC2+/FISH negative, by administering and ADC comprising i) an anti-HER2 antibody with CDR sequences of Disitamab vedotin, ii) an mc-vc-pAB linker that attaches to the antibody up to eight times via sulfhydryl conjugation and the linking site is the interchain disulfide bond of the antibody, iii) the cytotoxic molecule MMAE. One of ordinary skill would be motivated to treat HER2-low patients established as IHC1+ or IHC2+/FISH negative because this is a known metric for identifying this patient population known in the art, as evidenced by Study Details _ NCT03052634. There would be a reasonable expectation of success combining a method of identifying the HER2-low patient population and a method of treating HER2-low expressing patients because of the successful results taught by Xu.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 38-39 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-8, 12, 15, 16, 25, 36, 38, 40, 42, 55, 57, 89, and 99 of 19/564737 in view of Behrens (Methods for site-specific drug conjugation to antibodies, 2014, Landes Bioscience, pgs. 46-53), as applied to claim 24 above, in further view of Jiang (Preclinical safety profile of disitamab vedotin:a novel anti-HER2 antibody conjugated with MMAE, 2019, Toxicology Letters, pgs. 30-37; instant IDS), as evidenced by Precision FDA ( “Disitamab Vedotin”, 2026, Precision FDA, pgs. 1-11; see instant PTO-892).
The modified method of ‘737 and Behrens teaches a method of treating HER2-low expressing breast cancer patients by administering an ADC comprising i) an anti-HER2 antibody with CDR sequences of Disitamab vedotin, ii) an mc-vc-pAB linker that attaches to the antibody up to eight times via sulfhydryl conjugation and the linking site is the interchain disulfide bond of the antibody, iii) the cytotoxic molecule MMAE.
The modified method of Behrens and ‘737 does not teach that the ADC has a
DAR of 4.
The teachings of Jiang are described above.
It would be obvious to modify the ADC composition in the modified method of treating HER2-low expressing breast cancer patients of Behrens and ‘737 with an ADC DAR value of 4, as taught by Jiang to arrive at teach a method of treating HER2-low expressing breast cancer by administering an ADC comprising i) an anti-HER2 antibody with CDR sequences of Disitamab vedotin, ii) an mc-vc-pAB linker that attaches to the antibody via sulfhydryl conjugation and the linking site is the interchain disulfide bond of the antibody, iii) an average of four cytotoxic MMAE molecules. One of ordinary skill in the art would be motivated to modify the ADC with a DAR value of 4 because Behrens teaches that 2-4 drugs per antibody is the ideal level of drug loading. There would be a reasonable expectation of success based on the successful preclinical results of Disitamab vedotin taught by Jiang , which has a DAR of 4.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 40 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-8, 12, 15, 16, 25, 36, 38, 40, 42, 55, 57, 89, and 99 of 19/564737 in view of Behrens (Methods for site-specific drug conjugation to antibodies, 2014, Landes Bioscience, pgs. 46-53), as applied to claim 24 above, in view of Lee, ( The histological diagnosis of metastases to the breast from extramammary malignancies, 2007, Journal of Clinical Pathology, pgs. 1333-1341), as evidenced by Precision FDA ( “Disitamab Vedotin”, 2026, Precision FDA, pgs. 1-11; see instant PTO-892).
The modified method of ‘737 and Behrens teaches a method of treating HER2-low expressing breast cancer patients by administering an ADC comprising i) an anti-HER2 antibody with CDR sequences of Disitamab vedotin, ii) an mc-vc-pAB linker that attaches to the antibody up to eight times via sulfhydryl conjugation and the linking site is the interchain disulfide bond of the antibody, iii) the cytotoxic molecule MMAE.
The modified method of Behrens and ‘737 does not teach that the MBC is established by histology.
Claim 36 of ‘737 teaches treating HER2-low expressing, unresectable MBC.
The teachings of Lee are above.
It would be obvious to modify the method of HER2-low expressing breast cancer of ‘737 and Behrens, to treat MBC that is unresectable, as taught by ‘737, by establishing MBC by histology, as taught by Lee, to arrive at a method of treating unresectable HER2-low expressing breast cancer, as established by histology by administering and ADC comprising i) an anti-HER2 antibody with CDR sequences of Disitamab vedotin, ii) an mc-vc-pAB linker that attaches to the antibody up to eight times via sulfhydryl conjugation and the linking site is the interchain disulfide bond of the antibody, iii) the cytotoxic molecule MMAE. One of ordinary skill in the art would be motivated to establish MBC by histology because Lee teaches standard histological features used in the art to diagnose MBC. There would be a reasonable expectation of success combining a known method of diagnosing MBC and a method of treating MBC.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 41-43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-8, 12,15, 25, 36, 38, 42, 57, 89, and 99 of 19/564737 in view of Behrens (Methods for site-specific drug conjugation to antibodies, 2014, Landes Bioscience, pgs. 46-53), as applied to claim 24 above, in view of Ghersi (A systematic review of taxane-containing regimens for metastatic breast cancer, 2005, British Journal of Cancer, pgs. 291-301; see intrant PTO-892), as evidenced by Precision FDA ( “Disitamab Vedotin”, 2026, Precision FDA, pgs. 1-11; see instant PTO-892).
The modified method of ‘737 and Behrens teaches a method of treating HER2-low expressing breast cancer patients by administering an ADC comprising i) an anti-HER2 antibody with CDR sequences of Disitamab vedotin, ii) an mc-vc-pAB linker that attaches to the antibody up to eight times via sulfhydryl conjugation and the linking site is the interchain disulfide bond of the antibody, iii) the cytotoxic molecule MMAE.
The modified method of ‘737 and Behrens does not teach that the subject previously received taxane systemic therapy.
The teachings of Ghersi are described above.
It would be obvious to combine the method of treating HER2-low expressing breast cancer of ‘737 and Behrens patients previously treated with taxane systemic therapy, as taught by Xu to arrive at a method of HER2-low expressing breast cancer by administering taxane chemotherapy before administering an ADC comprising i) an anti-HER2 antibody with CDR sequences of Disitamab vedotin, ii) an mc-vc-pAB linker that attaches to the antibody up to eight times via sulfhydryl conjugation and the linking site is the interchain disulfide bond of the antibody, iii) the cytotoxic molecule MMAE. One of ordinary skill would be motivated to pretreat patients with taxane systemic therapy because ‘737 teaches treating the patient with chemotherapy and Ghersi teaches that taxane-containing therapy is just as if not more effective than non-taxane-containing chemotherapies. There would be a reasonable expectation of success because two known methods of HER2 breast cancer over the course of a patient’s treatment protocol.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 44 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-8, 12,15, 25, 36, 38, 42, 57, 89, and 99 of 19/564737 in view of Behrens (Methods for site-specific drug conjugation to antibodies, 2014, Landes Bioscience, pgs. 46-53), as applied to claim 24 above, in view of Xu (Abstract PD4-06: Early clinical development of RC48-ADC in patients with HER2 positive metastatic breast cancer, 2020, Cancer Res. Pgs. 1-2; see instant PTO-892), as evidenced by Precision FDA (“Disitamab Vedotin”, 2026, Precision FDA, pgs. 1-11; see instant PTO-892).
The modified method of ‘737 and Behrens teaches a method of treating HER2-low expressing breast cancer patients by administering an ADC comprising i) an anti-HER2 antibody with CDR sequences of Disitamab vedotin, ii) an mc-vc-pAB linker that attaches to the antibody up to eight times via sulfhydryl conjugation and the linking site is the interchain disulfide bond of the antibody, iii) the cytotoxic molecule MMAE.
The modified method of ‘737 and Behrens does not teach that the subject has been previously treated with trastuzumab.
The teachings of Xu are described above.
The teachings of Tarantino are above.
It would be obvious to combine the method of treating HER2-low expressing breast cancer of ‘737 and Behrens with the HER2-low expressing BC patient population that has been previously treated with trastuzumab of Tarantino to arrive at a method of treating HER-2 low expressing breast cancer patients who have previously received trastuzumab, by administering an ADC comprising i) an anti-HER2 antibody with CDR sequences of Disitamab vedotin, ii) an mc-vc-pAB linker that attaches to the antibody up to eight times via sulfhydryl conjugation and the linking site is the interchain disulfide bond of the antibody, iii) the cytotoxic molecule MMAE. One of ordinary skill would be motivated to combine the modified method ‘737 and Behrens with the HER-2 BC patient population previously treated with trastuzumab, as taught by Xu, because 1) Xu teaches that the majority of patients treating the Disitamab vedotin ADC had been previously treated with trastuzumab, and 2) Tarantino teaches limited clinical value of trastuzumab for this patient population, meaning patients who had received trastuzumab likely still require treatment. There would be a reasonable expectation of success treating the HER2-low BC patient population that has received trastuzumab treatment with the modified method of ‘737 and Behrens because of the successful results taught by Xu.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 24-27, 32, 37 41, 42, 44 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 16, 18, and 19 of U.S. Patent No. US 10,087,260 in view of Xu (Abstract PD4-06: Early clinical development of RC48-ADC in patients with HER2 positive metastatic breast cancer, 2020, Cancer Res. Pgs. 1-2) , as evidenced by Precision FDA (“Disitamab Vedotin”, 2026, Precision FDA, pgs. 1-11; see instant PTO-892), Behrens (Methods for site-specific drug conjugation to antibodies, 2014, Landes Bioscience, pgs. 46-53; see instant PTO-892), and Study Details _ NCT03052634 (“A Study of RC48-ADC in Subjects With Advanced Breast Cancer” ClinicalTrials.gov, 2016; see instant PTO-892).
Claims 16, 18, 19 of ‘260 teach a method of treating trastuzumab-resistant breast cancer by administering an effective amount of a pharmaceutical composition. Claim 1 of ‘260 teaches that the pharmaceutical composition can include an antibody conjugate with anti-HER2 antibody comprising CDR SEQ ID NOs: 1-6 (which are the same as instant claim 32 CDRs SEQ ID NOs:11-16). Regarding instant claim 37, as evidenced by Precision FDA, the CDRs of SEQ ID NOs: 1-6 are the CDRs of Disitamab Vedotin. Claims 1-11, 13-15 of ‘260 teach that the conjugate can include i) formula Ab-(L-U)n, ii) an mc-vc-pAB linker covalently linked to the antibody through thiol, iii) up to eight cytotoxic MMAE molecules. As evidenced by Behrens, attaching a mc-vc-pAB linker to an antibody through thiol necessarily requires sulfhydryl conjugation and the linking site to be an interchain disulfide bond (Fig 1., Fig. 1 caption, pg. 47).
‘260 does not teach a method for treating HER2-low expressing breast cancer as established by IHC1+ or IHC2+/FISH negative.
The teachings of Xu are above. As evidenced by Study Details _ NCT03052634, the HER2-low patients treated in Xu were established by IHC1+ or IHC2+/FISH negative.
It would be obvious to modify the method of treating breast cancer by trastuzumab-resistant breast cancer by administering an effective amount of a HER2 ADC, as taught by the reference application, to treat HER2-low expressing breast cancer established by IHC1+ or IHC2+/FISH negative, as taught by Xu, in order to arrive at a method of treating HER2-low expressing breast cancer established by IHC1+ or IHC2+/FISH negative, by administering an effective amount of an ADC wherein the antibody comprises CDR SEQ ID NOs: 1-6 of the reference application, an mc-vc-pAB linker covalently linked to the antibody through sulfhydryl conjugation and at the linking site of an interchain disulfide bond of the antibody, and up to eight cytotoxic MMAE molecules, to patients who had previously received trastuzumab systemic treatment. One of ordinary skill in the art would be motivated to use the method of reference application to treat the HER2-low expressing breast cancer patient population established by IHC1+ or ICH2+/FISH negative because of the successful results taught by Xu. For this reason, there would also be a reasonable expectation of success.
Claims 37-39 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 16, 18, and 19 of U.S. Patent No. US 10,087,260 in view of Xu (Abstract PD4-06: Early clinical development of RC48-ADC in patients with HER2 positive metastatic breast cancer, 2020, Cancer Res. Pgs. 1-2; see instant PTO-892), in further view of Jiang (Preclinical safety profile of disitamab vedotin:a novel anti-HER2 antibody conjugated with MMAE, 2019, Toxicology Letters, pgs. 30-37; instant IDS), as evidenced by Precision FDA (“Disitamab Vedotin”, 2026, Precision FDA, pgs. 1-11; see instant PTO-892), Behrens (Methods for site-specific drug conjugation to antibodies, 2014, Landes Bioscience, pgs. 46-53; see instant PTO-892) and Study Details _ NCT03052634 (“A Study of RC48-ADC in Subjects With Advanced Breast Cancer” ClinicalTrials.gov, 2016; see instant PTO-892).
The modified method of ‘260 and Xu, as evidenced by Precision FDA, Behrens, and Study Details _ NCT03052634, teaches a method of treating HER2-low expressing breast cancer established by IHC1+ or IHC2+/FISH by administering an effective amount of an ADC wherein the antibody comprises CDR SEQ ID NOs: 1-6 of the reference application (which are the same as instant claim 32 CDRs comprising SEQ ID NOs:11-16), an mc-vc-pAB linker covalently linked to the antibody through sulfhydryl conjugation and at the linking site of an interchain disulfide bond of the antibody, and up to eight cytotoxic MMAE molecules, to patients who had previously received trastuzumab systemic treatment.
The modified method does not teach an average DAR value of the ADC of 4.
The teachings of Jiang are above.
It would be obvious to modify the ADC composition in the method of treating HER2-low expressing breast cancer of Xu and ‘260 to arrive at method of treating HER2-low expressing breast cancer established by IHC1+ or IHC2+/FISH by administering an effective amount of an ADC wherein the antibody comprises CDR SEQ ID NOs: 1-6 of the reference application, an mc-vc-pAB linker covalently linked to the antibody through sulfhydryl conjugation and at the linking site of an interchain disulfide bond of the antibody, and a DAR value of 4, to patients who had previously received trastuzumab systemic treatment. One of ordinary skill would be motivated to limit the DAR to an average of four drugs per antibody, because high drug loading can lead to rapid drug clearance from the body. There would be a reasonable expectation of success treating HER2-low expressing breast cancer established by IHC1+ or IHC2+/FISH with an ADC comprising Disitamab Vedotin CDRs, a linker and an average of four MMAE cytotoxic molecules because of the successful results taught by Xu and Jiang.
Claims 40 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 16, 18, and 19 of U.S. Patent No. US 10,087,260 in view of Xu (Abstract PD4-06: Early clinical development of RC48-ADC in patients with HER2 positive metastatic breast cancer, 2020, Cancer Res. Pgs. 1-2; see instant PTO-892),in further view of Lee ( The histological diagnosis of metastases to the breast from extramammary malignancies, 2007, Journal of Clinical Pathology, pgs. 1333-1341; see instant PTO-892), as evidenced by Precision FDA (“Disitamab Vedotin”, 2026, Precision FDA, pgs. 1-11; see instant PTO-892), Behrens (Methods for site-specific drug conjugation to antibodies, 2014, Landes Bioscience, pgs. 46-53; see instant PTO-892), and Study Details _ NCT03052634 (“A Study of RC48-ADC in Subjects With Advanced Breast Cancer” ClinicalTrials.gov, 2016; see instant PTO-892).
The modified method of ‘260 and Xu, as evidenced by Precision FDA, Behrens, and Study Details _ NCT03052634, teaches a method of treating HER2-low expressing breast cancer established by IHC1+ or IHC2+/FISH by administering an effective amount of an ADC wherein the antibody comprises CDR SEQ ID NOs: 1-6 of the reference application (which are the same as instant claim 32 CDRs comprising SEQ ID NOs:11-16), an mc-vc-pAB linker covalently linked to the antibody through sulfhydryl conjugation and at the linking site of an interchain disulfide bond of the antibody, and up to eight cytotoxic MMAE molecules, to patients who had previously received trastuzumab systemic treatment.
The modified method of ‘260 and Xu does not explicitly teach that the breast cancer is MBC as established by histology and is unresectable.
The teachings of Xu are above.
The teachings of Lee are above.
It would be obvious to modify the method of treating HER2-low expressing breast cancer of Xu and ‘260 to treat unresectable metastatic breast cancer as established by histology to arrive at a method of treating HER2-low expressing breast cancer established by IHC1+ or IHC2+/FISH negative, wherein the cancer is metastatic as established by histology, and is unresectable by administering an effective amount of an ADC wherein the antibody comprises a) CDR SEQ ID NOs: 1-6 of the reference application, b) an mc-vc-pAB linker covalently linked to the antibody through sulfhydryl conjugation and at the linking site of an interchain disulfide bond of the antibody, and c) up to eight cytotoxic MMAE molecules, to patients who had previously received trastuzumab systemic treatment. One of ordinary skill would be motivated to treat the unresectable metastatic breast cancer patient population with the modified method of ‘260 and Xu, because Xu teaches treating patients who had visceral metastatis of breast cancer with the ADC Disitamab vedotin, which has the same structure and CDRs as the ADC composition of ‘260 and Xu. While the visceral metastasis of MBC taught by Xu does not categorically mean the patients’ cancer was unresectable, one of ordinary skill in the art would recognize that the patient population with unresectable MBC greatly overlaps with the patient population of visceral metastasis of MBC because when the cancer spread is extensive or to certain regions of the body, it becomes unresectable; thus, it would be obvious for one of ordinary skill to arrive at the claimed invention of treating unresectable MBC based on the teachings of visceral metastasis by Xu. There would be a reasonable expectation of success combining a method of treating a patient population, namely the modified method of reference application ‘260 and Xu treating HER2-low expressing patients, with a method of identifying said patient population, namely using histological features of MBC taught by Lee.
Claims 43 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 16, 18, and 19 of U.S. Patent No. US 10,087,260 in view of Xu (Abstract PD4-06: Early clinical development of RC48-ADC in patients with HER2 positive metastatic breast cancer, 2020, Cancer Res. Pgs. 1-2; see instant PTO-892), in further view of Ghersi (A systematic review of taxane-containing regimens for metastatic breast cancer, 2005, British Journal of Cancer, pgs. 291-301; see intrant PTO-892), as evidenced by Precision FDA (“Disitamab Vedotin”, 2026, Precision FDA, pgs. 1-11; see instant PTO-892), Behrens (Methods for site-specific drug conjugation to antibodies, 2014, Landes Bioscience, pgs. 46-53; see instant PTO-892), and Study Details _ NCT03052634 (“A Study of RC48-ADC in Subjects With Advanced Breast Cancer” ClinicalTrials.gov, 2016; see instant PTO-892).
The modified method of ‘260 and Xu, as evidenced by Precision FDA, Behrens, and Study Details _ NCT03052634, teaches a method of treating HER2-low expressing breast cancer established by IHC1+ or IHC2+/FISH by administering an effective amount of an ADC wherein the antibody comprises CDR SEQ ID NOs: 1-6 of the reference application (which are the same as instant claim 32 CDRs comprising SEQ ID NOs:11-16), an mc-vc-pAB linker covalently linked to the antibody through sulfhydryl conjugation and at the linking site of an interchain disulfide bond of the antibody, and up to eight cytotoxic MMAE molecules, to patients who had previously received trastuzumab systemic treatment.
The modified method of ‘260 and Xu does not explicitly state that subject has been previously treated with taxane systemic therapy.
The teachings of Ghersi are above.
It would be obvious to combine the method of treating HER2-low expressing breast cancer of Xu and ‘260 with patients who had previously received taxane systemic therapy, as taught by Xu. One of ordinary skill would be motivated to combine HER2-low BC patient population that had previously received taxane therapy with the method of treating this patient population of Xu and ‘260 because Xu specifically teaches that the majority of patients receiving Disitamab vedotin, which has the same structure and CDRs as the ADC in modified ‘260 and Xu, had already received two treatments of chemotherapy. There would be a reasonable expectation of success because Ghersi teaches that taxane-containing therapy is just as if not more effective than non-taxane-containing chemotherapies.
Claims 45-56 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 16, 18, and 19 of U.S. Patent No. US 10,087,260 in view of Xu (Abstract PD4-06: Early clinical development of RC48-ADC in patients with HER2 positive metastatic breast cancer, 2020, Cancer Res. Pgs. 1-2; see instant PTO-892), in further view of Jiang (Preclinical safety profile of disitamab vedotin:a novel anti-HER2 antibody conjugated with MMAE, 2019, Toxicology Letters, pgs. 30-37; instant IDS), as evidenced by Precision FDA (“Disitamab Vedotin”, 2026, Precision FDA, pgs. 1-11; see instant PTO-892), Behrens (Methods for site-specific drug conjugation to antibodies, 2014, Landes Bioscience, pgs. 46-53; see instant PTO-892), and Study Details _ NCT03052634 (“A Study of RC48-ADC in Subjects With Advanced Breast Cancer” ClinicalTrials.gov, 2016; see instant PTO-892).
The modified method of ‘260 and Xu, as evidenced by Precision FDA, Behrens, and Study Details _ NCT03052634, teaches a method of treating HER2-low expressing breast cancer established by IHC1+ or IHC2+/FISH by administering an effective amount of an ADC wherein the antibody comprises CDR SEQ ID NOs: 1-6 of the reference application (which are the same as instant claim 32 CDRs comprising SEQ ID NOs:11-16), an mc-vc-pAB linker covalently linked to the antibody through sulfhydryl conjugation and at the linking site of an interchain disulfide bond of the antibody, and up to eight cytotoxic MMAE molecules, to patients who had previously received trastuzumab systemic treatment.
The modified method of ‘260 and Xu does not explicitly state administering the composition intravenously at a dose of 2.0 mg/kg every two weeks.
The teachings of Jiang are above.
The teachings of Xu are above.
It would be obvious to modify the ADC dosing regimen in the method of treating HER2-low expressing breast cancer of the reference application ‘260 and Xu to administer the ADC intravenously at a dose of 2.0 mg/kg every two weeks, as taught by Jiang and Xu, to arrive at a method of treating HER2-low expressing breast cancer by intravenously administering an ADC comprising a) CDR SEQ ID NOs: 1-6 of the reference application (which are the same as instant claim 32 CDRs comprising SEQ ID NOs:11-16), b) an mc-vc-pAB linker covalently linked to the antibody through sulfhydryl conjugation and at the linking site of an interchain disulfide bond of the antibody, and c) up to eight cytotoxic MMAE molecules, to patients who had previously received trastuzumab systemic treatment, at a dose of 2.0 mg/kg every two weeks. One of ordinary skill in the art would have been motivated to administer the modified Disitamab vedotin composition at this dosing regimen because of a) successful preclinical results of a repeated intravenous dosing regimen of Disitamab vedotin in monkeys taught by Jiang and b) successful teaching of a 2.0mg/kg dose every two weeks of Disitamab vedotin for human patients taught by Xu. There would be a reasonable expectation of success treating HER2-low expressing BC patients established by IHC1+ or IHC2+/FISH who had previously been treated with trastuzumab systemic treatment, with the modified Disitamab vedotin of Jiang, Behrens, and Xu based on Xu ’s teachings that a 2.0mg/kg dose of Disitamab vedotin had successful results for this patient population.
Conclusion
No claims allowed.
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/MICHELLE CALLAHAN BUCCINI/Examiner, Art Unit 1675
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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