DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of species in claims 13 and 14 drawn to methods for the treatment of cancer wherein the cancer is a cancer with HER2 over-expression in the reply filed on 5/11/2026 is acknowledged.
Claims 1-20 are pending in the instant application.
Claims 1, 3-7, 13-15, and 17-20 are being examined on the merits.
Claims 2, 8-12, and 16 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 5/11/2026.
Applicant is reminded that upon the cancelation of claims to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - Sequences appearing in the specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c). Amino acid sequences of 4 or more amino acids require a sequence identifier. See the following pages of the instant disclosure:
Page 11, sequences depicting CDR1, CDR2, and CDR3 for heavy chain;
Pages 12-13, sequences depicting CDR1, CDR2, and CDR3 for light chain, heavy chain sequence of trastuzumab, light chain sequence of trastuzumab.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Specification
The disclosure is objected to because of the following informalities:
The following pages are missing sequence identifiers:
Page 11, sequences depicting CDR1, CDR2, and CDR3 for heavy chain;
Pages 12-13, sequences depicting CDR1, CDR2, and CDR3 for light chain, heavy chain sequence of trastuzumab, light chain sequence of trastuzumab.
Appropriate correction is required.
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 13 and 14 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 13 fails to include all the limitations of claim 2 to which it depends. Claim 14 depends on claim 13, and therefore also fails to incorporate by reference all the limitations of the claim to which it refers. 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 Interpretation
Claim 13 is interpreted as depends on claim 1. It should be noted that such treatment does not relieve Applicants of the responsibility of responding to this rejection. Moreover, if the intended meaning of the claim is different than that posited by the Examiner, additional 35 U.S.C. § 112 and prior art rejections may be readily applied in a subsequent office action
For the purpose of compact prosecution, claim 13 is interpreted to depend from claim 1.
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, 3-7, 13-15, and 17-20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 1, 3-5, 7, 13, 15, and 20, recite exemplary language that renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. Specifically, the phrase “preferably” renders the claim indefinite in regards to instant claims 1, 3-5, 7, 13, 15, and 20, because it is unclear whether the limitations following the phrase are part of the claimed invention. Claims 6, 14, and 17-19 are dependent on claim 1.
Furthermore, claim 1 recite exemplary language that renders the claim indefinite because it is unclear whether the limitation is part of the claimed invention. Specifically, the limitation following “e.g.” renders the claim indefinite in regards to instant claim 1, because it is unclear whether the limitation following the term “e.g.” is part of the claimed invention. Claims 3-5, 7, 13, 15, and 20 are dependent on claim 1.
Claim 1 recites that “A is a moiety obtained by the removal of n amino groups from an anti-HER2 antibody or an active fragment or variant thereof…” However, it is unclear what regions and sequences of the recited anti-HER2 antibody Applicant intends to cover by “active fragment or variant thereof”.
Regarding instant claims 13 and 14, claim 13 is indefinite as being incomplete by its dependence on withdrawn claim 2. Thus, the metes and bound of the claim are unclear as there is no antecedent basis for the limitations in the withdrawn base claims. See MPEP 608.01(n). Claim 14 is dependent on claim 13.
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, 3-7, 13-15, and 17-20 are 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 treatment of a cancer with HER2 over-expression comprising administering to a subject in need thereof a therapeutically effective amount of an antibody-drug conjugate of Formula (I), does not reasonably provide enablement for prevention of a cancer with HER2 over-expression, comprising administering to a subject in need thereof a therapeutically effective amount of an antibody-drug conjugate of Formula (I). 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.
Claim 1 is for a method of preventing cancer, but the specification and the state of the art do not teach a method to prevent cancer by to a subject in need thereof a therapeutically effective amount of an antibody-drug conjugate of Formula (I). Claims 3-7, 13-15, and 17-20 are further dependent on claim 1 without requiring treatment.
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:
The breadth of the claims;
The nature of the invention;
The state of the prior art;
The level of one of ordinary skill;
The level of predictability in the art;
The amount of direction provided by the inventor;
The existence of working examples; and
The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Scope of the claimed genus and nature of the invention.
Claims 1, 3-7, 13-15, and 17-20 are for a method of treating or preventing cancer with HER2 over-expression comprising administering to a subject in need thereof a therapeutically effective amount of an antibody-drug conjugate of Formula (I), a pharmaceutically acceptable salt, a stereoisomer or a metabolite thereof, or a solvate of the foregoing,
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wherein A is a moiety obtained by the removal of n amino groups from an anti-HER2 antibody or an active fragment or variant thereof, preferably a moiety obtained by the removal of n amino groups from trastuzumab or pertuzumab, and n is an integer from 1-10.
State of the Relevant Art; level of one of ordinary skill; and level of predictability of the art.
Cancer has a wide variety of causes, from environmental and/or developmental exposure to ionizing radiation and/or chemical exposure in addition to some types viral and bacterial exposure (Lichtman, 2017, The Oncologist, 22(5): 542–548). Even though cancer is featured by the infinite cell proliferation, its pathogenesis is extremely complex and related to many mechanisms. In general, the hallmarks of cancer consist of ten biological capabilities during the development of cancers, namely sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, tumor-promoting inflammation, genome instability and mutation, evading immune destruction and reprogramming energy metabolism (Hanahan et al, 2011, Cell, 144(5): 646-674, Figures 1 and 3). More than 100 types of cancer have been identified which are typically termed for the organs or tissues where they occur. Hanahan taught over the past decade, tumors have increasingly been recognized as organs whose complexity approaches and may even exceed that of normal healthy tissues (page 661, right column second to last paragraph). Hanahan taught many human tumors are histopathologically diverse, containing regions demarcated by various degrees of differentiation, proliferation, vascularity, inflammation, and/or invasiveness (page 662, left column, first paragraph).
Clinical trials aimed at proving preventative cancer activity attributable to a specific intervention are largely infeasible, due to the impossibly large number of subjects and an equally impossible long timeframe. Although cancer is a common disease, specific types of cancer are still relatively infrequent events in an otherwise healthy population. Therefore, trials with cancer incidence as endpoints would necessarily involve several thousands of subjects followed for several decades. Such logistic difficulties have precluded cancer prevention trials with cancer incidence as an endpoint in all but a selected few malignancies for treatments such as tamoxifen and finasteride (Lee et al, 2011, Nature Reviews Cancer, 11: 211-218; page 211, left column last paragraph). Lee further taught although many reports have suggested benefits and targets of phytochemicals, these reports mainly rely on cell and animal models (page 216, right column last paragraph). Lee taught that in order to apply phytochemicals as personalized cancer preventive agents, the effects of phytochemicals in humans will need to be assessed (page 216, right column last paragraph).
Human epidermal growth factor receptor 2 (HER2) is expressed in many tissues and its major role in these tissues is to facilitate excessive/uncontrolled cell growth and tumorigenesis (Iqbal et al, “Human Epidermal Growth Factor Receptor 2 (HER2) in Cancers: Overexpression and Therapeutic Implications”, September 7 2014, Molecular Biology International, 2014(852748):1-9; page 1, §Introduction). Iqbal also teaches that overexpression of the HER2 gene occurs in approximately 15-30% of breast cancers, and increased understanding of HER2 biology has now shown that HER2 overexpression occurs in other forms of cancers as well, such as stomach, ovary, uterine serous endometrial carcinoma, colon, bladder, lung, uterine cervix, head and neck, and esophagus page 2, right column, first paragraph). Overall, Iqbal discloses that HER2 overexpression had a negative impact and was associated with poorer survival in the majority of cancers (pages 2-4, §3: HER2 Overexpression in Cancers). Iqbal further teaches that although HER2 overexpression was found to correlate with poor outcome in other cancers, HER2-directed therapies have not been successful in cancers other than breast and gastric/gastroesophageal cancers; therefore, HER2 directed therapies are recommended in only breast and gastric/gastroesophageal cancers until further prognostic significance is provided in other types of cancers (page 7, §Conclusion).
Yan also teaches that HER2 overexpression is an effective therapeutic target in breast and gastric cancer (Yan et al, “HER2 expression status in diverse cancers: review of results from 37,992 patients”, February 25 2015, Cancer Metastasis Rev, 34:157-164; page 157, Abstract). Yan further discloses HER2 protein expression in various malignancies, wherein HER2 protein 3+ expression by IHC was demonstrated in a subset of virtually all examined carcinomas derived from epithelial origin; however, interestingly, HER2 protein 3+ expression was very rare in malignancies from non-epithelial origin (Table 1; Figure 1). Yan concludes that overall, 2.7% of all cancers tested were IHC 3+positive, wherein high levels of HER2 were seen in a subset of patients with most epithelial malignancies examined. Furthermore, Yan discloses that with the data presented herein as well as the advent of numerous, potent small molecule inhibitors, antibodies, and other agents that target HER2, it may be worthwhile to enrich clinical trials using HER2-targeting agents with patients that have HER2-positive tumors other than breast and gastric (page 162, right column, last paragraph).
Summary of Species disclosed in the original specification; the amount of direction provided by the inventor, existence of working examples; and quality of experimentation needed to make or use the invention based on the content of the disclosure.
The specification only identifies cancer treatment in Examples 1-11 (pages 23-27), showing the efficacy of the ADC on the treatment of different types of cancers, such as gallbladder cancer, parotid gland carcinoma, upper gastrointestinal cancer, intrahepatic cholangiocarcinoma, head and neck cancer, breast cancer, gastroesophageal junction adenocarcinoma, ovarian cancer, bladder cancer, colorectal cancer, and lung cancer. The instant specification taught the following as summarized in the table below:
*CR=Complete Response; PR=Partial Response; SD=Stable Disease
Cancer Type
HER2 expression in Patients
Response
Gallbladder Cancer
IHC 3+
PR
Parotid Gland Carcinoma
IHC 1+, IHC 2+, IHC 3+
PR
Upper Gastrointestinal Cancer
HER2 amplification
PR
HER2 mutation
SD
Intrahepatic Cholangiocarcinoma
HER2 expression
SD
Head and Neck Cancer
IHC 2+, IHC 3+
SD
Breast Cancer
HER2 amplification
SD
IHC 3+
PR
IHC 3+, IHC 2+/FISH positive
CR/PR/SD
IHC 3+, IHC 2+/FISH positive, IHC 2+/FISH negative, IHC 1+
PR/SD
Gastroesophageal Junction Adenocarcinoma
HER2 amplification
SD
Ovarian Cancer
HER2 amplification/mutation
SD
Bladder Cancer
IHC 3+
SD
Colorectal Cancer
IHC 3+
PR
Lung Cancer
HER2 amplification
SD
HER2 mutation
PR
The instant specification concludes that compound I-1 exhibited good efficacy in treatment of patients suffering from breast cancer with HER2 over-expression (page 24, Example 6) and lung cancer with HER2 amplification or mutation (page 27, Example 11).
Conclusion
The Applicant does not have enablement for a method of preventing cancer, comprising administering to a subject in need thereof a therapeutically effective amount of an antibody-drug conjugate of Formula (I) in claims 1, 3-7, 13-15, and 17-20.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 3-7, 13, and 17-20 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Song et al (WO2019214492A1, priority to 5/11/2018, published on 11/14/2019; hereinafter Song).
Regarding instant claims 1, 3, and 4, Song teaches a method of treating a cancer that is insensitive to or ineffective in the treatment of a drug targeted to HER2, the method comprising administering to an individual in need thereof a therapeutically effective amount of conjugate of formula (I):
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, wherein A is an anti-HE2 antibody or a group obtained by removing n amino groups in an active fragment or variant thereof, preferably, A is a group obtained by removing n amino groups from trastuzumab, and n is an integer of 1-8 (page 6, ¶ [0058]-[0061]), a pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or a solvate of the foregoing (page 6, ¶ [0057]). Song also teaches that the cancer that is insensitive to the drug treatment of HER2 is HER2-positive breast cancer (page 7, ¶ [0071]).
Regarding instant claim 5, Song teaches the treatment comprising administering to the patient a therapeutically effective amount of a conjugate of formula (I), a pharmaceutically acceptable salt, stereoisomer, or metabolite thereof or a solvate of the foregoing administered at a dose of 0.1-15mg/kg body weight (page 7, ¶ [0079]).
Regarding instant claim 6, Song teaches formula (I-1), which has the structure:
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, wherein A1 is the group obtained by removing 2 amino groups from trastuzumab (page 6, ¶ [0065]-[0066]).
Regarding instant claim 7, any observed pharmacological effects of the recited composition is an invariable aspect, see MPEP 2112.01 (“Products of identical chemical composition can not have mutually exclusive properties.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id.”).
Regarding instant claim 13, Song discloses that the cancer is preferably a HER2-positive breast cancer (page 7, ¶ [0071]), wherein Song defines "HER2 high expression", "HER2 overexpression" and "HER2 positive" are used interchangeably and generally refer to HER2 expression level in clinical detection of IHC 2+/FISH positive (i.e. IHC 2+ and simultaneous FISH positive) or IHC 3+, wherein FISH positive refers to FISH detection results showing HER2 gene amplification (page 6, ¶ [0054]).
Regarding instant claim 17, Song teaches that the HER2-positive cancer that is insensitive to drug therapy targeting HER2 or targeted HER2 treatment includes HER2-positive cancer with drug resistance to the drug targeting HER2, wherein the cancer comprises breast cancer such as metastatic breast cancer, locally advanced breast cancer or recurrent breast cancer (page 7, ¶ [0068]).
Regarding instant claims 18 and 19, Song teaches using trastuzumab drugs and/or treatment using T-DM1 drugs, wherein breast cancer is treated by using
Trastuzumab wherein the first load dose being 4 mg/kg body weight, followed by maintaining a dose of 2 mg/kg body weight per week, for 12 weeks (and paclitaxel or docetaxel combined) or 18 weeks (and docetaxel/carboplatin combination), followed by maintaining a dose of 6 mg/kg body weight per triweek intravenous infusion for 52 weeks (page 7, ¶ [0074], [0076]).
Regarding instant claim 20, Song discloses that the treatment further comprises the step of assessing, prior to administration, whether the cancer of the patient is not sensitive to a drug treatment targeting HER2 comprising the steps of treating HER-2 positive cancer patients using a targeted HER2 drug and monitoring whether a patient has drug resistance to the targeted HER2 drug (page 8, ¶ [0080]-[0082]), wherein the drug targeting HER2 comprises an anti-HER2 antibody-based drug, such as a monoclonal antibody, an antibody-drug conjugate (ADC), and a bispecific antibody (page 7, ¶ [0070]).
Claims 1, 3-7, 13, 15, and 18 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Xue et al (CN106729743A, Priority to 11/23/2015, Published on 5/31/2017, IDS entered on 9/7/2023; hereinafter Xue).
Regarding instant claims 1, 3-4, 6, 13, and 15, Xue teaches a method for treating cancer, the method comprising administering to a patient in need thereof an antibody-drug conjugate comprising the general formula (I), a pharmaceutically acceptable salt or stereoisomer thereof, or a solvate of the antibody-drug conjugate, salt or stereoisomer (page 3, sixth paragraph “In a sixth aspect…”), wherein the most preferred antibody drug conjugates of general formula (I) is Formula (I-1):
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, wherein A is A is trastuzumab (page 17, first and second paragraphs). Xue also teaches that the cancer includes, but is not limited to, breast cancer, gastric cancer, ovarian cancer, non-small cell lung cancer, and liver cancer, particularly breast cancer, such as breast cancer with high expression of ErbB2 (page 18, last paragraph “In the fourth aspect…”).
Regarding instant claims 5 and 18, Xue teaches that trastuzumab, T-DM-1 or the antibody drug conjugate I-1 were administered at a dose of 3mg/kg of body weight in breast cancer mouse models, wherein the tumor growth rate TGI(%) was used to evaluate the antitumor efficacy of the antibody drug conjugates (page 24-25, Example 4; Tables 1 and 2).
Regarding instant claim 7, any observed pharmacological effects of the recited composition is an invariable aspect, see MPEP 2112.01 (“Products of identical chemical composition cannot have mutually exclusive properties.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id.”).
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Song et al (WO2019214492A1, priority to 5/11/2018, published on 11/14/2019; hereinafter Song), and further in view of Glisson (Glisson et al, “HER2 Expression in Salivary Gland Carcinomas: Dependence on Histological Subtype”, February 10 2004, Clinical Cancer Research, 10:944-946; hereinafter Glisson).
Regarding instant claim 14, the teachings of Song are discussed above in the 102 rejection.
However, Song does not teach a method for treatment of a cancer with HER2 over-expression comprising administering to a subject in need thereof a therapeutically effective amount of an antibody-drug conjugate of Formula (I), a pharmaceutically acceptable salt, a stereoisomer or a metabolite thereof, or a solvate of the foregoing, wherein the cancer with HER2 expression is adenoid cystic carcinoma with HER2 over-expression.
The deficiency is resolved by Glisson.
Glisson teaches expression of HER2 in recurrent salivary gland carcinomas as part of a clinical trial to define the clinical activity of trastuzumab, a recombinant monoclonal antibody directed against HER2, in these tumors, (page 944, right column, last paragraph). Glisson also discloses the frequency of HER2 expression in salivary gland carcinomas, which was detected by either immunostaining or fluorescence in situ hybridization, wherein rates of 7 and 56% in adenoid cystic have been documented. In fact, in two reports, Glisson teaches that overexpression of HER2 was an independent marker of poor prognosis in mucoepidermoid and adenoid cystic carcinomas (page 945, left column, second paragraph). Glisson further teaches the frequency of overexpression in the three most common subtypes (adenoid cystic, adenocarcinoma, and mucoepidermoid), was only 8% (8 of 103), wherein, in contrast, salivary duct carcinoma appears to strongly overexpress HER2 in the majority of cases (page 946, left column, second paragraph of §Discussion; Table 2).
Regarding instant claim 14, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify the method of treating a cancer comprising administering to an individual in need thereof a therapeutically effective amount of conjugate of formula (I), a pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or a solvate of the foregoing, wherein the cancer with HER2 expression is a cancer with HER2 over-expression as taught by Song to include the cancer with HER2 over-expression is adenoid cystic carcinoma, a type of salivary gland carcinoma as taught by Glisson. This is obvious because, Song teaches a method of treating a cancer comprising administering to an individual in need thereof a therapeutically effective amount of conjugate of formula (I):
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, wherein A is an anti-HE2 antibody or a group obtained by removing n amino groups in an active fragment or variant thereof, preferably, A is a group obtained by removing n amino groups from trastuzumab, and n is an integer of 1-8, a pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or a solvate of the foregoing, wherein the cancer is HER2 positive, such as HER2 positive breast cancer, and Glisson teaches the frequency of HER2 expression in salivary gland carcinomas, which was detected by either immunostaining or fluorescence in situ hybridization, wherein overexpression of HER2 was an independent marker of poor prognosis in adenoid cystic carcinomas. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant method for treatment of a cancer with HER2 over-expression comprising administering to a subject in need thereof a therapeutically effective amount of the instant antibody-drug conjugate of Formula (I), a pharmaceutically acceptable salt, a stereoisomer or a metabolite thereof, or a solvate of the foregoing, wherein the cancer with HER2 expression is a cancer with HER2 overexpression, wherein the cancer with HER2 overexpression is adenoid cystic carcinoma.
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.
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Claims 1, 3, and 6 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 12 and 23-27 of copending Application No. 18/324,511 (US20230293536A1; hereinafter ‘511) in view of Naito et al (US 2016/0333112 A1, Priority to January 31, 2014; hereinafter Naito).
Claims 12 and 23 of ‘511 teach an antibody drug conjugate (ADC) wherein the ADC composition is formula I-1:
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wherein A is trastuzumab. which is identical to Formula I-1 disclosed in the instant application (see instant claims 1 and 6). Claim 24 of ‘511 teach a pharmaceutical composition comprising ADC of formula I-1, and claim 25-27 of ‘511 discloses a method for the treatment of cancer, comprising administering to a patient in need thereof the pharmaceutical composition, wherein the cancer is breast cancer (see instant claims 1, 3, and 6).
However, ‘511 does not teach formula I-1, wherein A is moiety obtained by the removal of n amino groups from trastuzumab.
The deficiency is resolved by Naito.
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), wherein the anti-HER2 ADC targeting antibody as trastuzumab (page 10, paragraph 109, Figure 1 and 2). Naito further teaches that 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, and it is also known that two amino acid residues (glycine and lysine) at the carboxyl terminus of the heavy chain of an antibody produced in a cultured mammalian cell are deleted and a proline residue newly located at the carboxyl terminus is amidated. However, Naito discloses that 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 31, ¶ [0218]).
Regarding instant claims 1, 3, and 6, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify the method for the treatment of cancer, comprising administering to a patient in need thereof the pharmaceutical composition comprising formula I-1, wherein the cancer is breast cancer as taught by ‘511 to include that n amino groups are removed from trastuzumab as taught by Naito
This is obvious because, ‘511 teaches a method for the treatment of cancer, comprising administering to a patient in need thereof the pharmaceutical composition comprising formula I-1 wherein the cancer is breast cancer, and Naito teaches that it is known that the lysine residue at the carboxyl terminus of the heavy chain of an antibody produced in a cultured mammalian cell is deleted, and 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. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant method for treatment of a cancer with HER2 over-expression comprising administering to a subject in need thereof a therapeutically effective amount of the instant antibody-drug conjugate of Formula (I), a pharmaceutically acceptable salt, a stereoisomer or a metabolite thereof, or a solvate of the foregoing, wherein the cancer is breast cancer.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 3-7, -13, 15, and 19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5, 11, 14-20, and 22 of copending Application No. 17/471,953 (US20220008553A1; hereinafter ‘953) in view of Naito et al (US 2016/0333112 A1, Priority to January 31, 2014; hereinafter Naito).
Claim 1 of ‘953 teaches a method for the treatment of cancer, comprising administering to a patient in need thereof an antibody-drug conjugate represented by Formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, or a solvate of the foregoing,
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, wherein (i) A is an anti-ErbB2 antibody or an active fragment or variant thereof; (ii) X is N; (iii) Y is N or CR1, and R1 is H or C1-C10 alkyl; (iv) L is a divalent linker; (v) D is a cytotoxic agent group; (vi) a is an integer selected from the group consisting of 2-10; and all the cytotoxic agent groups are conjugated to the light chain of the antibody. Claims 2-3 and 5 of ‘953 teach that the anti-ErbB2 antibody is an anti-human ErbB2 antibody comprised of CDR1, CDR2, CDR3 of the heavy and light chains of trastuzumab, and claim 11 of ‘953 teach that the ADC of claim 1 is represented by Formula I-1:
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, wherein A is trastuzumab (see instant claims 1 and 6). Claims 14 and 15 teach the method for the treatment of cancer, comprising administering to a patient in need thereof the ADC of formula (I), wherein the cancer is carcinoma, or more specifically breast cancer (see instant claims 3 and 4). Claims 16-18 of ‘953 further recite that the cancer is ErbB2-overexpressing cancer, wherein the ErbB2-overexpressing cancer is breast cancer (see instant claim 13) or liver cancer (see instant claim 15). Claims 19-20 of ‘953 teach the dosage of the ADC and the frequency of the ADC that is administered for the treatment (see instant claims 5 and 19), and claim 22 of ‘953 teach the pharmacologic effects of the ADC (see instant claim 7).
However, ‘953 does not teach formula (I) or I-1, wherein A is moiety obtained by the removal of n amino groups from trastuzumab.
The deficiency is resolved by Naito.
The teachings of Naito are discussed above.
Regarding instant claims 1, 3-7, 13, 15, and 19, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify the method for the treatment of cancer, comprising administering to a patient in need thereof the ADC comprising formula I-1 as taught by ‘953 to include that n amino groups are removed from trastuzumab as taught by Naito. This is obvious because, ‘953 teaches a method for the treatment of cancer, comprising administering to a patient in need thereof the ADC comprising formula I-1, and Naito teaches that it is known that the lysine residue at the carboxyl terminus of the heavy chain of an antibody produced in a cultured mammalian cell is deleted, and 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. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant method for treatment of a cancer with HER2 over-expression comprising administering to a subject in need thereof a therapeutically effective amount of the instant antibody-drug conjugate of Formula (I), a pharmaceutically acceptable salt, a stereoisomer or a metabolite thereof, or a solvate of the foregoing.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 3-7, and 20 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 7, 9, 16-17, 19, and 22 of U.S. Patent No. 12,150,944 B2 (hereinafter ‘944).
Claims 1, and 19 of ‘944 teach a method of treating a cancer insensitive or irresponsive to a treatment with a HER2-targeting agent, comprising administering a therapeutically effective amount of a conjugate of Formula (I), a pharmaceutically acceptable salt or stereoisomer thereof, or a solvate of the foregoing to a subject in need thereof,
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, wherein A is a moiety obtained after the removal of n amino groups from an anti-HER2 antibody or an active fragment thereof, and n is an integer of 1, 2, 3, 4, 5, 6, 7, or 8 (see instant claim 1). Claim 2 of ‘944 further teach that the conjugate of Formula (I) has the structure represented by Formula (I-1),
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wherein A1 is a moiety obtained after the removal of 2 amino groups from Trastuzumab (see instant claim 6). Claim 3 of ‘944 also recites that the cancer is breast cancer comprising a HER2 positive breast cancer insensitive or irresponsive to a treatment with a HER2-targeting agent (see instant claims 3 and 4). Claims 9 and 17 of ‘944 recite the dose of the ADC administered for treatment (see instant claim 5), and claims 7, 16, and 22 recite the HER2-targeting agent that the patient has received prior to the treatment (see instant claim 20).
Regarding instant claim 7, any observed pharmacological effects of the recited composition is an invariable aspect, see MPEP 2112.01 (“Products of identical chemical composition cannot have mutually exclusive properties.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id.”).
Therefore, although the claims at issue are not identical, they are not patentably distinct from each other.
Conclusion
No claims are allowed.
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/J.H./Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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