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 .
Claims Status
The amendments and remarks filed 12/16/2025 are acknowledged and entered.
Claims 1-2, 9, 16, 19-20, 24-25, 29, 32, 34-35, 43-44, 48, 51, 54-56, 70-71, 75, 78, 83-85, 99-100, 104, 107, 110-111, 113-115, 123-124, 128, 131-133, 141-142, 146, 149-151, 165-166, 170, 174-176, 180, 182-185, 190, 196, 201, 203-205, 210, and 214-215 are pending.
Claims 3-8, 10-15, 17-18, 21-23, 26-28, 30-31, 33, 36-42, 45-47, 49-50, 52-53, 57-69, 72-74, 76-77, 79-82, 86-98, 101-103, 105-106, 108-109, 112, 116-122, 125-127, 129-130, 134-140, 143-145, 147-148, 152-164, 167-169, 171-173, 177-179, 181, 186-189, 191-195, 197-200, 202, 206-209, 211-213, and 216-219 are canceled.
Claim 196 is amended.
Applicant’s election without traverse of the following species in the reply filed on 12/16/2025 is acknowledged: SEQ ID NOs: 9-11 for the CDRs H1-H3 and SEQ ID NOs: 12-14 for the CDRs L1-L3, respectively, -Aa-Ww-Yy- for the linker wherein -A- is a stretcher unit, a is 1; -W-is an amino acid unit, w is 2; and-Y-is a spacer unit, y is 1, 3-4 units of MMAE per antibody or antigen binding fragment thereof, the ADC is formulated at about 10 mg/ml in a pharmaceutical composition comprising about 1.4 mg/ml histidine, about 2.31 mg/ml histidine hydrochloride monohydrate, about 0.2 mg/ml polysorbate-20, and about 55 mg/ml trehalose dihydrate, and wherein the pH of the pharmaceutical composition is about 6.0 at 25°C.
Claims 1-2, 9, 16, 19-20, 24-25, 29, 32, 34-35, 43-44, 48, 51, 54-56, 70-71, 75, 78, 83-85, 99-100, 104, 107, 110-111, 113-115, 123-124, 128, 131-133, 141-142, 146, 149-151, 165-166, 170, 174-176, 180, 182-185, 190, 196, 201, 203-205, 210, and 214-215 are under examination.
Priority
The instant application is a 371 of PCT/US2020/061923 and claims priority to provisional application to 62/940,209 and 62/944,890. Priority is given with the earliest effective filing date of 11/25/2019.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 12/21/2022 and 12/16/2025 are in compliance with the provisions of 37 CFR 1.97, except where noted. Accordingly, the information disclosure statement is being considered by the examiner.
Foreign Patent Documents B01 – B17 on the 12/21/2022 IDS are not being considered because they are not attached. Non-Patent Literature Document C80 on the 12/21/2022 IDS is not considered because it is not of sufficient quality to read.
Notably, the disclosure statement filed lists a Search Report. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
Drawings
The drawings are objected to because Figures 4A-4H have pixelated backgrounds and therefore do not meet the requirements of 37 CFR 1.84(a)(1) which requires that “india ink, or its equivalent that secures solid black lines, must be used for drawings”. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because it contains embedded hyperlinks and/or other forms of browser-executable code (see paragraphs [0002], [00312], [00338], [00349], [00363], [00380], [00396], [00414], [00429], [00430], and [00821] of the specification). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http://, www., or other browser-executable code. See MPEP § 608.01.
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 1-2, 9, 16, 19-20, 24-25, 29, 32, 34-35, 43-44, 48, 51, 54-56, 70-71, 75, 78, 83-85, 99-100, 104, 107, 110-111, 113-115, 123-124, 128, 131-133, 141-142, 146, 149-151, 165-166, 170, 174-176, 180, 182-185, 190, 196, 201, 203-205, 210, and 214-215 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 and 203 recite the limitation “wherein the antibody or antigen binding fragment thereof comprises a heavy chain variable region comprising complementarity determining regions (CDRs) comprising the amino acid sequences of the CDRs of the heavy chain variable region set forth in SEQ ID NO:22 and a light chain variable region comprising CDRs comprising the amino acid sequences of the CDRs of the light chain variable region set forth in SEQ ID NO:23.”
It is well known to those skilled in the art that antibodies utilize various numbering schemes to facilitate comparison and analysis of their variable regions. The most commonly used schemes include Kabat, Chothia, and IMGT. These schemes differ in their approach to defining regions, particularly the hypervariable regions (CDRs) that are crucial for antigen binding. Specifically, these different CDR identification methods may often identify radically different stretches as CDRs, indicating that CDRs are not well defined [Sela-Culang et al., 2013 (instant PTO-892); see Conclusion]. For example, Sela-Culang shows in Table 3 below, a comparison of CDR regions using different numbering methods demonstrating the significant difference between the amino acid sequences depending on what numbering scheme is utilized.
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730
680
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Greyscale
The instant specification fails to clarify the issue, disclosing that the CDRs may be defined by any well-known numbering system, including but not limited to, Kabat, Chothia, AbM, contact, or IMGT [see 00253 of the instant specification]. The CDRs herein include overlaps and subsets of amino acid residues defined in different ways.
Therefore, without the amino acid sequences of each CDR region defined by SEQ ID NO or numbering scheme, one of ordinary skill in the art would not know the boundaries of the CDR regions set forth in the recited VH SEQ ID NO: 22 and VL SEQ ID NO: 23.
Note: Claims 170 and 210 do set forth specific sequences for each of the heavy chain and light chain CDRs 1-3.
Further, claims 1 and 203 recite the limitation “wherein the subject has urothelial cancer”. It is unclear if the urothelial cancer is the cancer to be treated or if the subject has urothelial cancer in addition to another cancer that is to be treated. Therefore, the scope of these claims is indefinite.
Claims 2, 9, 16, 19-20, 24-25, 29, 32, 34-35, 43-44, 48, 51, 54-56, 70-71, 75, 78, 83-85, 99-100, 104, 107, 110-111, 113-115, 123-124, 128, 131-133, 141-142, 146, 149-151, 165-166, 174-176, 180, 182-185, 190, 196, 201, 204-205, and 214-215 are included in the rejection because they depend from or otherwise require all the limitations of a rejected independent claim.
Claim 1 recites the limitation “a first regimen comprising an effective amount of an ADC” and claim 2 recites “the first regimen comprises an ADC at a dose of about 1.25 mg/kg.” It is unclear what Applicant intends by “regimen”. “Regimen” is not explicitly defined in the specification and a regimen is not a single dose of something, as set forth in claims 1 and 2, rather, a regimen dictates a specific schedule, dosage, and duration of a therapeutic [see NIH; instant PTO-892].
Claims 2, 9, 16, 19-20, 24-25, 29, 32, 34-35, 43-44, 48, 51, 54-56, 70-71, 75, 78, 83-85, 99-100, 104, 107, 110-111, 113-115, 123-124, 128, 131-133, 141-142, 146, 149-151, 165-166, 174-176, 180, 182-185, 190, 196, and 201, which depend from claim 1, and therefore indefinite for the same reasons. It is noted that claims 16, 24, 29, 35, 43, 48, 56, 70, 75, 85, 99, 104, 111, 115, 123, 128, 133, 141, 146, 151, and 165 also recite “regimen” and thus, have the same issues as set forth above.
Note: Claim 203 also recites “regimen” however, the claim sets forth a specific regimen comprising steps a – d. Thus, claim 203 and its dependent claims are not indefinite.
Claims 2, 35, 43, 56, 70, 85, 99, 111, 115, 123, 133, 141, 151, 165, 184, 190, 196, 201, and 215 recite the limitation “about”. Applicant has provided an explicit definition for “about” meaning within 20%, within 15%, within 10%, within 9%, within 8%, within 7%, within 6%, within 5%, within 4%, within 3%, within 2%, within 1%, or less of a given value or range [see paragraph 00298 of the Specification]. However, the metes and bounds for “about” are dependent on the interpretation of others for determining what is the acceptable range. Given a single value, one person of ordinary skill in the art could determine that the range is 15%. Yet, another person of ordinary skill in the art could determine that the range is 5%, leading to two different interpretations on if the claim infringes with “about.” Therefore, these claims are indefinite.
Claim 16 recites the limitation “determining the blood glucose level in the subject” in each of the alternative options 1) – 4). It is unclear where in the method steps, whether before, during, or after the regimen comprising the administration of the ADC, the determination of the blood glucose is to take place. If before, then in option 1 of claim 16, the method of treating set forth in instant claim 1 would never take place. Therefore, the scope of this claim is indefinite.
Claim 19, which depends from claim 16, recites the limitation “2) the subject has hyperglycemia; and/or 3) the subject has hyperglycemia and diabetic ketoacidosis (DKA); and/or 4) the subject additionally has a higher body mass index and/or a higher baseline A1C.” It is unclear if options 2) – 4) apply to the subject prior to the administration of the ADC or after the administration of the ADC. Therefore, the scope of this claim is indefinite.
Claim 25 recites determining the blood glucose level at various intervals. It is unclear if the blood glucose is determined at these intervals before, during, or after the administration of the ADC. Therefore, the scope of this claim is indefinite.
Claim 29 recites the limitation “determining peripheral neuropathy in the subject” in each of the alternative options 1) – 4). It is unclear where in the method steps, whether before, during, or after the regimen comprising the administration of the ADC, the determination of the blood glucose is to take place. If before, then in option 1 of claim 29, the method of treating set forth in instant claim 1 would never take place. Therefore, the scope of this claim is indefinite.
Claims 35, 56, 85, 115, 133, 151 recite the limitation “the condition for the administration of the second regimen has been satisfied.” First, there is insufficient antecedent basis for “the condition” in the claims. The lack of antecedent basis arises from claim’s 35 dependence on claim 29, claim 56’s dependence on claim 48, claim 85’s dependence on claim 75, claim 115’s dependence on claim 104, claim 133’s dependence on claim 128, and claim 151’s dependence on claim 146 where a “condition” is not mentioned. Additionally, it is unclear what is intended by “satisfied”. The term “satisfied” is subjective. One person of ordinary skill in the art could determine the condition is satisfied, while yet another person of ordinary skill in the art could determine that the condition is not satisfied, leading to two different interpretations on if the claim infringes with “satisfied.” Therefore, these claims are indefinite.
For examination purposes, the Examiner has interpretated “the condition” of claim 35 as referring to the peripheral neuropathy, “the condition” of claim 56 as referring to the skin condition, “the condition” of claim 85 as referring to the non-hematologic toxicity, “the condition” of claim 115 as referring to the hematologic toxicity, “the condition” of claim 133 as referring to the fatigue, and “the condition” of claim 151 as referring to the diarrhea.
Claim 44 recites determining the peripheral neuropathy at various intervals. It is unclear if the peripheral neuropathy is determined at these intervals before, during, or after the administration of the ADC. Therefore, the scope of this claim is indefinite.
Claim 48 recites the limitation “determining a skin reaction in the subject” in each of the alternative options 1) – 4). It is unclear where in the method steps, whether before, during, or after the regimen comprising the administration of the ADC, the determination of the skin reaction is to take place. If before, then in option 1 of claim 48, the method of treating set forth in instant claim 1 would never take place. Therefore, the scope of this claim is indefinite.
Claim 71 recites determining the skin condition at various intervals. It is unclear if the skin condition is determined at these intervals before, during, or after the administration of the ADC. Therefore, the scope of this claim is indefinite.
Claim 75 recites the limitation “determining the presence of non-hematologic toxicity in the subject” in each of the alternative options 1) – 4). It is unclear where in the method steps, whether before, during, or after the regimen comprising the administration of the ADC, the determination of the presence of non-hematologic toxicity is to take place. If before, then in option 1 of claim 75, the method of treating set forth in instant claim 1 would never take place. Therefore, the scope of this claim is indefinite.
Claims 100 recites determining the non-hematologic toxicity level at various intervals. It is unclear if the non-hematologic toxicity is determined at these intervals before, during, or after the administration of the ADC. Therefore, the scope of this claim is indefinite.
Claim 104 recites the limitation “determining the presence of hematologic toxicity in the subject” in each of the alternative options 1) – 4). It is unclear where in the method steps, whether before, during, or after the regimen comprising the administration of the ADC, the determination of the hematologic toxicity is to take place. If before, then in option 1 of claim 104, the method of treating set forth in instant claim 1 would never take place. Therefore, the scope of this claim is indefinite.
Claim 128 recites determining the blood hematologic toxicity at various intervals. It is unclear if the hematologic toxicity is determined at these intervals before, during, or after the administration of the ADC. Therefore, the scope of this claim is indefinite.
Claim 128 recites the limitation “determining fatigue in the subject” in each of the alternative options 1) – 4). It is unclear where in the method steps, whether before, during, or after the regimen comprising the administration of the ADC, the determination of the fatigue is to take place. If before, then in option 1 of claim 128, the method of treating set forth in instant claim 1 would never take place. Therefore, the scope of this claim is indefinite.
Claim 142 recites determining the fatigue at various intervals. It is unclear if the fatigue is determined at these intervals before, during, or after the administration of the ADC. Therefore, the scope of this claim is indefinite.
Claim 146 recites the limitation “determining diarrhea in the subject” in each of the alternative options 1) – 4). It is unclear where in the method steps, whether before, during, or after the regimen comprising the administration of the ADC, the determination of the diarrhea is to take place. If before, then in option 1 of claim 128, the method of treating set forth in instant claim 1 would never take place. Therefore, the scope of this claim is indefinite.
Claim 166 recites determining the diarrhea at various intervals. It is unclear if the diarrhea is determined at these intervals before, during, or after the administration of the ADC. Therefore, the scope of this claim is indefinite.
Claim Rejections - 35 USC § 112(a)
Written Description
Claims 176, 180, and 182-184 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 claims are drawn to a method of preventing or treating cancer comprising administering to the subject an effective amount of an ADC wherein the ADC comprises an antibody or antigen binding fragment thereof that binds to 191P4D12 conjugated to MMAE. Claims 176 adds the limitation of wherein the antigen binding fragment is a fully human antibody and claim 184 adds the limitation of wherein the antibody is a fully human monoclonal antibody.
The claims encompass human antibodies. However, the specification teaches that the antibody is produced by Chinese hamster ovary (CHO) cells [00705].
There is no disclosure of a fully human antibody nor any expectation that a
human antibody would comprise the same complementary determining regions (CDRs)
as those disclosed in the instant application because the antibodies were made in CHO cells. One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian fibroblast growth
factors (FGFs) were found to be unpatentable due to lack of written description for that
broad class. The specification provided only the bovine sequence. In the same manner,
disclosure of antibodies and antibody sequence produced in CHO cells provides no salient information regarding the sequences produced in a human.
Accordingly, as applicant does not appear to be in possession of a fully human
antibody with the claimed sequences, the disclosure as a whole fails to adequately
describe a human antibody. Thus, a claim to such an antibody fails to meet the written
description requirements.
Claims 180 and 182-183, which depend from claims 176 and 184, respectively, fail to meet the written description requirement for the same reasons.
Enablement
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 1-2, 9, 16, 19-20, 24-25, 29, 32, 34-35, 43-44, 48, 51, 54-56, 70-71, 75, 78, 83-85, 99-100, 104, 107, 110-111, 113-115, 123-124, 128, 131-133, 141-142, 146, 149-151, 165-166, 170, 174-176, 180, 182-185, 190, 196, 201, 203-205, 210, and 214-215 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 a method of treating a 191P4D12 (i.e. Nectin-4) expressing cancer, does not reasonably provide enablement for preventing or treating any cancer. 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.
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation’.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added). The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and
Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed most recently in Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v.
Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008). See also In re Cortright, 49 USPQ2d 1464, 1466 and Bristol-Myers Squibb Co. v. Rhone-Poulenc Rorer Inc., 49 USPQ2d 1370.
The factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). Among these factors are: (1) the nature or the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary. When the above factors are weighed, it is the examiner’s position that one skilled in the art could not practice the invention without undue experimentation. Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
(1) The nature of the invention and (5) The breadth of the claims:
Claim 1 is drawn to a method of preventing or treating cancer in a human subject, comprising administering to the subject a first regimen comprising an effective amount of an antibody drug conjugate (ADC), wherein the subject has urothelial cancer. Claim 203 is drawn to a method of treating cancer in a subject, comprising administering a treatment regimen to the subject, comprising administering an ADC, wherein the subject has urothelial cancer. The claims are broad and inclusive of all types of cancer and there is no requirement that the cancer to be treated is urothelial cancer. The breadth of the claim exacerbates the complex nature of the subject matter to which the present claims are directed. The claims are extremely broad due to the vast number of possible cancer types and tumor cell growth mechanisms represented by the phrase “preventing or cancer.” The instant specification does not provide any evidence that administration of the claimed ADC would treat any cancer. There if no support provided in the instant specification or in the prior or instant art that teaches or supports the ability to prevent any cancer encompassed by these broad claims. Cancer is not a single disease, or cluster of closely related disorders. There are hundreds of cancers, which have in common only some loss of controlled cell growth. Cancers are highly heterogeneous at both the molecular and clinical level, something seen especially in, for example, the cancers of the breast, brain and salivary glands. They can occur in pretty much every part of the body. Here are some assorted categories:
A. Leukemia is any malignant neoplasm of the blood-forming tissues. Leukemia can arise from many different sources. These include viruses such as EBV, which causes Burkitt's lymphoma, and HTLV-1, linked to certain T cell leukemias. Others are linked to genetic disorders, such as Fanconi's anemia, which is a familial disorder, and Down's Syndrome. Other leukemias are caused by exposure to carcinogens such as benzene, and some are actually caused by treatment with other neoplastic agents. Still other leukemias arise from ionizing radiation, and many are idiopathic. Leukemias also differ greatly in the morphology, degree of differentiation, body location (e.g. bone marrow, lymphoid organs, etc.) There are dozens of leukemias. There are B-Cell Neoplasms such as B-cell prolymphocytic leukemia and Hairy cell leukemia (HCL, a chronic Lymphoid leukemia). There are T-Cell Neoplasms such as T-cell prolymphocytic leukemia, aggressive NK cell leukemia, adult T cell leukemia/lymphoma (ATLL), and T-cell granular Lymphocytic leukemia. There are different kinds of acute myeloid leukemias (undifferentiated AML, acute myeloblastic, acute myelomonocytic leukemia, acute monocytic leukemias, acute monoblastic, acute megakaryoblastic (AmegL), acute promyelocytic leukemia (APL), and erythroleukemia). There is also lymphoblastic leukemia, hypocellular acute myeloid leukemia, Ph-/BCR- myeloid leukemia, and acute basophilic leukemia. Chromic leukemias include chronic lymphocytic leukemia (CLL, which exists in a B-cell and a T-cell type), prolymphocytic leukemia (PLL), large granular lymphocytic leukemia (LGLL, which goes under several other names as well), chronic myelogenous leukemia(CML), chronic myelomonocytic leukemia (CMML), chronic neutrophilic leukemia, chronic eosinophilic leukemia (CEL), and many others.
B. Breast cancers come in great variety. The most important category of breast cancers is the ductal cancers. These come in an assortment of types. Presently, these are divided into the following categories: intraductal (in situ); invasive with predominant intraductal component; invasive, NOS; Comedo; Inflammatory (IBC); medullary with lymphocytic infiltrate; mucinous carcinoma (colloid carcinoma); papillary carcinoma; scirrhous; tubular; and other. Another category is the Lobular breast cancers, which can be in situ, Invasive with predominant in situ component, and Invasive. There is Paget’s disease of the nipple, which can be also with intraductal carcinoma or with invasive ductal carcinoma. There is adenomyoepithelioma , a dimorphic tumor characterized by the presence of both epithelial and myoepithelial cells. There is lymphoma of the breast (which exists in both Non-Hodgkin's lymphoma of the breast and Hodgkin's disease of the breast forms). There are some sarcomas, including giant cell sarcoma of the breast, leiomyosarcoma of the breast, angiosarcoma of the breast, cystosarcoma phylloides, and liposarcoma of the breast. There are carcinoid tumors which can be primary carcinoid tumors of the breast, or can arise from nonmammary sources. There are breast salivary gland-like tumors, including acinic cell carcinoma, oncocytic carcinoma (mammary epithelial oncocytoma), and mucoepidermoid carcinoma. Other rare carcinomas include spindle cell carcinoma of the breast, squamous cell carcinoma of the breast, secretory carcinoma of the breast (juvenile secretory carcinoma), metaplastic carcinoma of the breast (a heterogeneous group of invasive breast cancers including types with squamous differentiation and those with heterologous elements), invasive micropapillary carcinoma of the breast, adenoid cystic carcinoma of the breast, cribriform carcinoma, myofibroblastoma of the breast (benign spindle stromal tumor of the breast) and glycogen-rich clear cell carcinoma of the breast. There are also nonmammary tumors, primarily adenocarcinomas, that can metastasize to the breast including bronchogenic carcinomas, malignant melanomas (primary and secondary), rhabdomyosarcomas, malignant mesotheliomas, thyroid carcinomas, renal cell carcinomas, malignant lymphomas, and gastrointestinal carcinomas (including those from the stomach, pancreas, esophagus, and colon). Complicating the treatment of breast carcinomas is the fact that a significant proportion of mammary carcinomas are not monoclonal.
C. Bladder cancers. Most cases of bladder cancers are transitional cell (urothelial) carcinoma, which includes non-invasive papillary urothelial carcinoma, flat urothelial carcinoma in situ (CIS), superficially invasive urothelial carcinoma, and muscle invasive tumors. Adenocarcinomas of the bladder include Primary Adenocarcinoma (urachal and non-urachal), Prostatic adenocarcinoma, Gastro-intestinal adenocarcinomas and Clear cell carcinoma. Squamous cell carcinomas include Verrucous carcinomas, and a secondary squamous cell carcinoma of the bladder, from the cervix. Small cell carcinomas include Primary small cell carcinoma of the bladder and the secondary small cell carcinoma ('reserve cell carcinoma') of the lung. Lymphomas include the primary lymphomas (Low grade B-cell lymphoma of MALT type, High grade B-cell lymphoma, and T-cell lymphoma), as well as secondary lymphomas, including mantle cell lymphomas. Melanomas include Primary Malignant melanoma of the bladder, and secondary ones. The sarcomas of the bladder are leiomyosarcoma, osteosarcoma and rhabdomyosarcoma. There is also a primary primitive neuroectodermal tumour (PNET) of the bladder, Paraganglioma (which can metastasize), nephrogenic adenoma, metastatic renal cell carcinoma of the bladder, and both primary and secondary (from the uterus) choriocarcinoma of the bladder.
Additionally, the term "preventing" is generally understood in the art to encompass a total protection from disease or injury. Thus, given the high level of
required effect, a high level of evidence showing prevention is also required. As noted
above, however, there are no working examples in the instant specification
demonstrating any therapy using the claimed treatment, nor any examples directed to
the palliative, preventative, or curative treatment of any cancer. Therefore, the instant specification does not provide evidence or substantial guidance commensurate in scope with the broadly claimed method and how to use the method to treat or prevent any cancer.
(2) The state of the prior art and (4) The predictability or unpredictability of the art:
While the state of the art is relatively high with regard to the treatment of specific cancer types, the state of the art with regard to treating cancer broadly is underdeveloped. In particular, there is no known anticancer agent that is effective against all cancer cell types. The cancer treatment art involves a very high level of unpredictability. While the state of the art is relatively high with regard to the treatment of specific cancers with specific agents, it has long been underdeveloped with regard to the treatment of cancers broadly. The lack of significant guidance from the present specification or prior art with regard to the actual treatment of all cancer cells in a mammal, including a human subject, with the claimed active ingredient makes practicing the claimed invention unpredictable.
With regard to cancer treatment, Bally et al. (US 5,595,756) stated, “Despite enormous investments of financial and human resources, no cure exists for a variety of diseases. For example, cancer remains one of the major causes of death. A number of bioactive agents have been found, to varying degrees, to be effective against tumor cells. However, the clinical use of such antitumor agents has been highly compromised because of treatment-limiting toxicities” [col. 1, lines 17-24].
The art indicates the difficulties in going from in vitro to in vivo for drug development for treatment of cancers. Auerbach et al., 2000 (instant PTO-892) indicates that one of the major problems in angiogenesis research has been the difficulty of finding suitable methods for assessing the angiogenic response. For example, the 96 well rapid screening assay for cytokinesis was developed in order to permit screening of hybridoma supernatants…In vitro tests in general have been limited by the availability of suitable sources for endothelial cells, while in vivo assays have proven difficult to quantitate, limited in feasibility, and the test sites are not typical of the in vivo reality [page 167, left column, 1st paragraph].
Furthermore, as taught by HogenEsch et al., 2012 (instant PTO-892), there is no single cell culture or in vivo cancer model that faithfully predicts the efficacy of anticancer drugs in human clinical trials. Cell culture approaches offer the advantage of human-derived cell lines or tissue fragments from primary tumors, but cannot mimic the complexity of the reciprocal interaction between the growing tumor and the co-evolving microenvironment. Xenografts in immunodeficient mice have limited added value over cell culture models as the lack of an intact immune system and insufficient interactions between the human tumor cells and mouse stromal cells do not recapitulate human cancers. Thus, the art recognizes that going from in vitro studies to in vivo studies for cancer drug developments are difficult to achieve.
Finally, the art teaches the unpredictability of antibody-based cancer immunotherapy. Christiansen et al., 2004 (instant PTO-892) teaches numerous factors that inhibit successful therapeutic application of antibodies including low or heterogeneous expression of target antigens by tumor cells, high background expression of target antigen on normal cells, host antibody immune responses to the antibodies themselves, insufficient antitumor response after antibody binding, as well as significant physical barriers preventing antibody binding or delivery to a solid tumor mass, including the vascular endothelium, stromal barriers, high interstitial pressure, and epithelial barriers [see Abstract, page 1493, column 2, page 1496, column 1, last paragraph through page 1498, column 2]. Topp et al., 1998 (instant PTO-892) also teaches the complications and unpredictability involved with treating tumors using antibody therapy. Topp teaches that there are several barriers to successful delivery of antibody drugs to extravascular sites of action within target tissues: the antibody drugs must be absorbed into the blood stream, carried by the circulatory system to the capillaries in the target tissue, cross the capillary endothelial cells and the underlying basement membrane that supports the capillary structure and penetrate through the matrix of cells and extracellular components that comprises the tissue itself, bind to the cell surface receptor, initiate endocytosis, encounter possible drug degradation and drug release. Additional connective tissue barriers may also be encountered [page 15, both columns, and Figure 1]. While some antibody drugs have been shown to be effective in vitro the results of clinical trials have been disappointing. The inability of the antibodies to penetrate the tumor mass could be a cause of this lack of clinical efficacy. Topp cautions against extrapolating in vitro results to in vivo therapy stating that the cell culture system has some limitations including a lack of well-developed extracellular matrix (“stroma”) that is present in many tumors. Normal components of tumor stroma include collagen, fibronectin and glycosaminoglycans [page 21, column 2]. Given the unpredictable art of treating tumors in vivo using antibody therapy, one of skill in the art could not predictably treat cancer in vivo comprising administering any antibody without undue experimentation.
Given Bally’s teaching of treatment-limiting toxicities in clinical use, Auerbach’s teaching that one of the major problems in angiogenesis research has been the difficulty of finding suitable methods for assessing the angiogenic response, HogenEsch’s teaching that there is no single cell culture or in vivo cancer model that faithfully predicts the efficacy of anticancer drugs in human clinical trial, and Christiansen’s and Topp’s teachings of the unpredictability of antibody-based cancer immunotherapy, these teachings collectively demonstrate that the treatment of cancer is highly unpredictable, if even possible for many cancers.
(6) the amount of direction or guidance presented; (7) the presence or absence of working examples:
There is a lack of working examples in the specification of treating all types of cancer encompassed by the instant claims or preventing any type of cancer. Applicant has provided evidence of treating lung cancer, breast cancer, and urothelial cancer [see Examples 1 and 3]. However, Applicant has not provided any substantive evidence of treating any type of cancer, other than lung, breast, and urothelial, with the claimed ADC, and further, has not provided any substantive evidence of preventing any type of cancer with the claimed ADC. Because the cancers encompassed by the instant claims are so disparate and no single cancer example can be representative of all the other encompassed cancers, a demonstration of treatment or support of a given condition does not provide support for the breadth of the claims.
In conclusion, the claimed invention does not provide enablement for treating all types of cancer encompassed by the instant claims or preventing any type of cancer. Thus for the reasons outlined above, the specification is not considered to be enabling for one skilled in the art to make and use the claimed invention as the amount of experimentation required is undue, due to the broad scope of the claims, the lack of guidance and working examples provided in the specification. Therefore, the specification is not representative of the instant claims and the specification is not fully enabled for the instant claims. In view of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention.
Claims 2, 9, 16, 19-20, 24-25, 29, 32, 34-35, 43-44, 48, 51, 54-56, 70-71, 75, 78, 83-85, 99-100, 104, 107, 110-111, 113-115, 123-124, 128, 131-133, 141-142, 146, 149-151, 165-166, 170, 174-176, 180, 182-185, 190, 196, 201, 204-205, 210, and 214-215, which depend from claim 1 and 203, respectively, are rejected for the same reasons set forth above.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-2, 9, 170, 174-176, 180, 182-185, 190, and 201 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by NCT03219333, 2018 (instant PTO-892).
Note: Applicant defines the claimed ADC as PADCEV (enfortumab vedotin-ejfv) [see paragraphs 00313, 00587, 00706 of the instant specification]. Therefore, the ADC taught by NCT03219333 is the same as the claimed ADC.
Regarding claims 1, 170, 174-175, NCT03219333 teaches a method for treatment of [human] patients with locally advanced or metastatic urothelial cancer who previously received immune checkpoint inhibitor (CPI) therapy [page 3, official title, pages 4-5, brief summary], and the patients have also received treatment with platinum-containing chemotherapy (Cohort 1) [page 5, detailed description], by administering enfortumab vedotin by intravenous infusion to the patients [page 7, Arms and Interventions].
Regarding claim 2, NCT03219333 teaches that the enfortumab vedotin is administered on days 1, 8, and 15 every 28 days [page 7, Arms and Interventions].
Regarding claim 9, NCT03219333 teaches that patients who received platinum could have been in the adjuvant or neoadjuvant setting [page 5, Detailed Description].
Regarding claims 176, 180, 182-185, 190, the enfortumab vedotin of NCT03219333 is necessarily a Fab, linked to MMAE, comprising the specific structural formula as set forth in instant claims 176, 180, 182-183, 185, 190, as evidenced by FDA, 2019 (instant PTO-892). FDA teaches that PADCEV (i.e. enfortumab vedotin-ejfv) is a nectin-4 directed ADC comprised of a fully human anti-Nectin-4 IgG1 kappa monoclonal antibody conjugated to the small molecule microtubule disrupting agent, MMAE via a protease-cleavable maleimidocaproyl valine-citrulline linker [page 11, Description]. FDA teaches that PADCEV is used in the clinical trial NCT03219333 [page 14, Clinical Studies].
Regarding claim 201, NCT03219333 teaches that the enfortumab vedotin is administered by intravenous (IV) infusion [page 7, Arms and Interventions].
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
Claims 1-2, 9, 16, 19-20, 24-25, 29, 32, 34-35, 43-44, 48, 51, 54-56, 70-71, 75, 78, 83-85, 99-100, 104, 107, 110-111, 113-115, 123-124, 128, 131-133, 141-142, 146, 149-151, 165-166, 170, 174-176, 180, 182-185, 190, 196, 201, 203-205, 210, and 214-215 are rejected under 35 U.S.C. 103 as being unpatentable over NCT03219333, 2018 (instant PTO-892), as applied to claims 1-2, 9, 170, 174-176, 180, 182-185, 190, and 201 above, in view of FDA, 2019 (instant PTO-892).
The teachings of NCT03219333 are above.
However, NCT03219333 does not specifically teach further comprising determining a blood glucose level (instant claim 16), peripheral neuropathy (instant claim 29), a skin reaction (instant claim 48), a non-hematologic toxicity (instant claim 75), a hematologic toxicity (instant claim 104), fatigue (instant claim 128), and diarrhea (instant claim 146).
Regarding claims 16, 19-20, 24-25, 29, 32, 34-35, 43-44, 48, 51, 54-56, 70-71, 75, 78, 83-85, 99-100, 104, 107, 110-111, 113-115, 123-124, 128, 131-133, 141-142, 146, 149-151, 165-166, 203-205, 210, and 214-215, FDA teaches adverse reactions of PADCEV administration include hyperglycemia, peripheral neuropathy, skin reactions, nonhematologic toxicities, hematologic toxicities [pages 2-3, Dose Modifications] fatigue, and diarrhea [page 7, Clinical Trials Experience]. FDA further teaches modifying the dosage of PADCEV or permanently discontinuing PADCEV depending on the measurements and severity of the adverse reactions [pages 2-3, Dose Modifications] and dose reductions in the subjects with the adverse reactions [page 7, Clinical Trials Experience]. FDA also teaches that the recommended dose of PADCEV is 1.25 mg/kg, up to a maximum of 125 mg for patients >/= 100kg, and teaches a dose reduction schedule [page 3, Table 2].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have determined a blood glucose level (instant claim 16), peripheral neuropathy (instant claim 29), a skin reaction (instant claim 48), a non-hematologic toxicity (instant claim 75), a hematologic toxicity (instant claim 104), fatigue (instant claim 128), and diarrhea (instant claim 146), as taught by FDA, in the method of NCT03219333. One would have been motivated to have determined a blood glucose level, peripheral neuropathy, a skin reaction, a non-hematologic toxicity, a hematologic toxicity, fatigue, and diarrhea after the administration of the enfortumab vedotin (PADCEV) as taught by NCT03219333 because FDA teaches that these are all adverse reactions of PADCEV administration. It further would have been obvious to have measured for these potential adverse reactions daily (as set forth in instant claims 25, 44, 71, 100, 124, 142, and 166) in order to monitor the reactions(s) development and/or progression. Additionally, it would have been obvious to have modified the dosage of PADCEV or discontinued the administration of PADCEV depending on the measurements and severity of the adverse reactions. One would have been motivated to have modified the dosage or discontinue the use of PADCEV depending on the adverse reactions because FDA teaches doing so. Therefore, this is a known parameter in the art.
Additionally, regarding the limitations of specific dosing and dosing schedules (which Applicant refers to as regimens), the art demonstrates that these are result effective variables of PADCEV and can be dependent on the adverse reactions. Through routine optimization, one of ordinary skill in the art would arrive at the specific dosing and dosing schedules as claimed in the instant claims. See MPEP 2144.05(II).
Claim 196 is included in this rejection because FDA teaches that PADCEV for injection is reconstituted in a solution containing 10 mg of the ADC, 1.4 mg histidine, 2.31 mg histidine hydrochloride monohydrate, 0.2 mg polysorbate 20, 55 mg trehalose dihydrate, with a pH of 6.0 [page 11, third paragraph].
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.
Claims 1-2, 9, 170, 174-176, 180, 182-185, 190, and 201 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 8,637,642, claims 1-5 of U.S. Patent No. 9,962,454, claims 1-38 of U.S. Patent No. 10,894,090, claims 1-32 of U.S. Patent No. 11,559,582, and claims 1-31 of U.S. Patent No. 12,257,340 in view of NCT03219333, 2018 (instant PTO-892).
Note: Applicant defines the claimed ADC as PADCEV (enfortumab vedotin-ejfv) [see paragraphs 00313, 00587, 00706 of the instant specification]. Further, SEQ ID NO: 7 (claimed in instant claim 175) of the instant application comprises SEQ ID NO: 22 (claimed in instant claims 1, 174, 203, and 214) of the instant application and SEQ ID NO: 8 (claimed in instant claim 175) of the instant application comprises SEQ ID NO: 23 (claimed in instant claims 1, 174, 203, and 214) of the instant application. Therefore, SEQ ID NOs: 7 and 8 comprise the specific CDRs set forth in instant claims 170 and 210. Sequence alignments for instant SEQ ID NOs: 7 and 8 aligned to each of the patent documents’ claimed SEQ ID NOs: 7 and 8 were completed with 100% sequence identity for each. See attached document for alignments. Therefore, the ADC taught by claims 1-11 of U.S. Patent No. 8,637,642, claims 1-5 of U.S. Patent No. 9,962,454, claims 1-38 of U.S. Patent No. 10,894,090, claims 1-32 of U.S. Patent No. 11,559,582, claims 1-31 of U.S. Patent No. 12,257,340, and NCT03219333 is the same as the claimed ADC.
Although the claims at issue are not identical, they are not patentably distinct from each other because claims 1-11 of U.S. Patent No. 8,637,642, claims 1-5 of U.S. Patent No. 9,962,454, claims 1-38 of U.S. Patent No. 10,894,090, claims 1-32 of U.S. Patent No. 11,559,582, and claims 1-31 of U.S. Patent No. 12,257,340 each are drawn to an identical antibody-drug conjugate comprising an antibody that binds to 191P4D12 (i.e. enfortumab vedotin; PADCEV) that is used in the instant claimed methods, and wherein a method of treating cancer comprising administering the ADC is disclosed in the specification and/or claims of each. See the decisions in Sun Pharmaceuticals v Eli Lily Fed Cir July 28, 2010; Geneva v GlaxoSmithKline 349, F.3d 1373; and Pfizer v Teva 518 F3d 1353 supporting the Office's use of disclosed utilities of compositions when applying double patenting rejections to method claims.
However, U.S. Patent No. 8,637,642, U.S. Patent No. 9,962,454, U.S. Patent No. 10,894,090, U.S. Patent No. 11,559,582, and U.S. Patent No. 12,257,340 do not specifically teach that the patient subject has urothelial cancer, has received an immune checkpoint inhibitor therapy and received a chemotherapy.
NCT03219333 teaches a method for treatment of [human] patients with locally advanced or metastatic urothelial cancer who previously received immune checkpoint inhibitor (CPI) therapy [page 3, official title, pages 4-5, brief summary], and the patients have also received treatment with platinum-containing chemotherapy (Cohort 1) [page 5, detailed description], by administering enfortumab vedotin by intravenous infusion to the patients [page 7, Arms and Interventions].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have administered the ADC as taught by each of U.S. Patent No. 8,637,642, U.S. Patent No. 9,962,454, U.S. Patent No. 10,894,090, U.S. Patent No. 11,559,582, and U.S. Patent No. 12,257,340 to the patient population of NCT03219333. One would have been motivated to have administered the ADC to treat the patient population of NCT03219333 because the ADC taught by each of the U.S. Patents is the same as that taught by NCT03219333. Administering the ADC to this patient population is a known parameters in the art, and therefore would have a reasonable expectation of success.
Claim 2 is included in this rejection because NCT03219333 teaches that the enfortumab vedotin is administered on days 1, 8, and 15 every 28 days [page 7, Arms and Interventions].
Claim 9 is included in this rejection because NCT03219333 teaches that patients who received platinum could have been in the adjuvant or neoadjuvant setting [page 5, Detailed Description].
Claims 176, 180, 182-185, and 190 are included in this rejection because the ADC (enfortumab vedotin) of U.S. Patent No. 8,637,642, U.S. Patent No. 9,962,454, U.S. Patent No. 10,894,090, U.S. Patent No. 11,559,582, U.S. Patent No. 12,257,340, and NCT03219333 is necessarily a Fab, linked to MMAE, comprising the specific structural formula as set forth in instant claims 176, 180, 182-183, 185, 190, as evidenced by FDA, 2019 (instant PTO-892). FDA teaches that PADCEV (i.e. enfortumab vedotin-ejfv) is a nectin-4 directed ADC comprised of a fully human anti-Nectin-4 IgG1 kappa monoclonal antibody conjugated to the small molecule microtubule disrupting agent, MMAE via a protease-cleavable maleimidocaproyl valine-citrulline linker [page 11, Description]. FDA teaches that PADCEV is used in the clinical trial NCT03219333 [page 14, Clinical Studies].
Claim 201 is included in this rejection because NCT03219333 teaches that the enfortumab vedotin is administered by intravenous (IV) infusion [page 7, Arms and Interventions].
Claims 1-2, 9, 16, 19-20, 24-25, 29, 32, 34-35, 43-44, 48, 51, 54-56, 70-71, 75, 78, 83-85, 99-100, 104, 107, 110-111, 113-115, 123-124, 128, 131-133, 141-142, 146, 149-151, 165-166, 170, 174-176, 180, 182-185, 190, 196, 201, 203-205, 210, and 214-215 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 8,637,642, claims 1-5 of U.S. Patent No. 9,962,454, claims 1-38 of U.S. Patent No. 10,894,090, claims 1-32 of U.S. Patent No. 11,559,582, and claims 1-31 of U.S. Patent No. 12,257,340 in view of NCT03219333, 2018 (instant PTO-892), as applied to claims 1-2, 9, 170, 174-176, 180, 182-185, 190, and 201 above, and further in view of FDA, 2019 (instant PTO-892).
The teachings of U.S. Patent No. 8,637,642, U.S. Patent No. 9,962,454, U.S. Patent No. 10,894,090, U.S. Patent No. 11,559,582, U.S. Patent No. 12,257,340, and NCT03219333 are above.
However, U.S. Patent No. 8,637,642, U.S. Patent No. 9,962,454, U.S. Patent No. 10,894,090, U.S. Patent No. 11,559,582, U.S. Patent No. 12,257,340, and NCT03219333 do not specifically teach further determining a blood glucose level (instant claim 16), peripheral neuropathy (instant claim 29), a skin reaction (instant claim 48), a non-hematologic toxicity (instant claim 75), a hematologic toxicity (instant claim 104), fatigue (instant claim 128), and diarrhea (instant claim 146).
Regarding claims 16, 19-20, 24-25, 29, 32, 34-35, 43-44, 48, 51, 54-56, 70-71, 75, 78, 83-85, 99-100, 104, 107, 110-111, 113-115, 123-124, 128, 131-133, 141-142, 146, 149-151, 165-166, 203-205, 210, and 214-215, FDA teaches adverse reactions of PADCEV administration include hyperglycemia, peripheral neuropathy, skin reactions, nonhematologic toxicities, hematologic toxicities [pages 2-3, Dose Modifications] fatigue, and diarrhea [page 7, Clinical Trials Experience]. FDA further teaches modifying the dosage of PADCEV or permanently discontinuing PADCEV depending on the measurements and severity of the adverse reactions [pages 2-3, Dose Modifications] and dose reductions in the subjects with the adverse reactions [page 7, Clinical Trials Experience]. FDA also teaches that the recommended dose of PADCEV is 1.25 mg/kg, up to a maximum of 125 mg for patients >/= 100kg, and teaches a dose reduction schedule [page 3, Table 2].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have determined a blood glucose level (instant claim 16), peripheral neuropathy (instant claim 29), a skin reaction (instant claim 48), a non-hematologic toxicity (instant claim 75), a hematologic toxicity (instant claim 104), fatigue (instant claim 128), and diarrhea (instant claim 146), as taught by FDA, in the method of NCT03219333, U.S. Patent No. 8,637,642, U.S. Patent No. 9,962,454, U.S. Patent No. 10,894,090, U.S. Patent No. 11,559,582, and U.S. Patent No. 12,257,340. One would have been motivated to have determined a blood glucose level, peripheral neuropathy, a skin reaction, a non-hematologic toxicity, a hematologic toxicity, fatigue, and diarrhea in the method of administering enfortumab vedotin (PADCEV) as taught by NCT03219333, U.S. Patent No. 8,637,642, U.S. Patent No. 9,962,454, U.S. Patent No. 10,894,090, U.S. Patent No. 11,559,582, and U.S. Patent No. 12,257,340 because FDA teaches that these are all adverse reactions of PADCEV administration. It further would have been obvious to have measured for these potential adverse reactions daily (as set forth in instant claims 25, 44, 71, 100, 124, 142, and 166) in order to monitor the reactions(s) possible development or progression. Additionally, it would have been obvious to have modified the dosage of PADCEV or discontinued the administration of PADCEV depending on the measurements and severity of the adverse reactions. One would have been motivated to have modified the dosage or discontinue the use of PADCEV depending on the adverse reactions because FDA teaches doing so.
Additionally, regarding the limitations of specific dosing and dosing schedules (which Applicant refers to as regimens), the art demonstrates that these are result effective variables of PADCEV and can be dependent on the adverse reactions. Through routine optimization, one of ordinary skill in the art would arrive at the specific dosing and dosing schedules as claimed in the instant claims. See MPEP 2144.05(II).
Claim 196 is included in this rejection because FDA teaches that PADCEV for injection is reconstituted in a solution containing 10 mg of the ADC, 1.4 mg histidine, 2.31 mg histidine hydrochloride monohydrate, 0.2 mg polysorbate 20, 55 mg trehalose dihydrate, with a pH of 6.0 [page 11, third paragraph]. Further, claims 1, 4-17 of U.S. Patent No. 12,257,340 teaches a pharmaceutical composition comprising the ADC with the same excipients in the same ranges as claimed.
Claims 1-2, 9, 170, 174-176, 180, 182-185, 190, and 201 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application Nos. 17/634,026, 18/025,349, 18/030,225, 18/682,886, and 18/724,594 in view of NCT03219333, 2018 (instant PTO-892).
Note: Applicant defines the claimed ADC as PADCEV (enfortumab vedotin-ejfv) [see paragraphs 00313, 00587, 00706 of the instant specification]. Note: Applicant defines the claimed ADC as PADCEV (enfortumab vedotin-ejfv) [see paragraphs 00313, 00587, 00706 of the instant specification]. Further, SEQ ID NO: 7 (claimed in instant claim 175) of the instant application comprises SEQ ID NO: 22 (claimed in instant claims 1, 174, 203, and 214) of the instant application and SEQ ID NO: 8 (claimed in instant claim 175) of the instant application comprises SEQ ID NO: 23 (claimed in instant claims 1, 174, 203, and 214) of the instant application. Therefore, SEQ ID NOs: 7 and 8 comprise the specific CDRs set forth in instant claims 170 and 210. Sequence alignments for instant SEQ ID NOs: 7 and 8 aligned to each of the patent documents’ claimed SEQ ID NOs: 7 and 8 were completed with 100% sequence identity for each. See attached document for alignments. Therefore, the ADC taught by copending Application Nos. 17/634,026, 18/025,349, 18/030,225, 18/682,886, and 18/724,594 and NCT03219333 is the same as the claimed ADC. See the decisions in Sun Pharmaceuticals v Eli Lily Fed Cir July 28, 2010; Geneva v GlaxoSmithKline 349, F.3d 1373; and Pfizer v Teva 518 F3d 1353 supporting the Office' s use of disclosed utilities of compositions when applying double patenting rejections to method claims.
The claims of copending Application Nos. 17/634,026, 18/025,349, 18/030,225, 18/682,886, and 18/724,594 each are drawn to an identical antibody-drug conjugate comprising an antibody that binds to 191P4D12 (i.e. enfortumab vedotin; PADCEV) that is used in the instant claimed methods, and wherein a method of treating cancer comprising administering the ADC is disclosed in the specification and/or claims of each.
However, copending Application Nos. 17/634,026, 18/025,349, 18/030,225, 18/682,886, and 18/724,594 do not specifically teach that the patient subject has urothelial cancer, has received an immune checkpoint inhibitor therapy and received a chemotherapy.
NCT03219333 teaches a method for treatment of [human] patients with locally advanced or metastatic urothelial cancer who previously received immune checkpoint inhibitor (CPI) therapy [page 3, official title, pages 4-5, brief summary], and the patients have also received treatment with platinum-containing chemotherapy (Cohort 1) [page 5, detailed description], by administering enfortumab vedotin by intravenous infusion to the patients [page 7, Arms and Interventions].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have administered the ADC as taught by each of copending Application Nos. 17/634,026, 18/025,349, 18/030,225, 18/682,886, and 18/724,594, to the patient population of NCT03219333. One would have been motivated to have administered the ADC to treat the patient population of NCT03219333 because the ADC taught by each of the U.S. Patents is the same as that taught by NCT03219333. Administering the ADC to this patient population is a known parameters in the art, and therefore would have a reasonable expectation of success.
Claim 2 is included in this rejection because NCT03219333 teaches that the enfortumab vedotin is administered on days 1, 8, and 15 every 28 days [page 7, Arms and Interventions].
Claim 9 is included in this rejection because NCT03219333 teaches that patients who received platinum could have been in the adjuvant or neoadjuvant setting [page 5, Detailed Description].
Claims 176, 180, 182-185, and 190 are included in this rejection because the ADC (enfortumab vedotin) of copending Application Nos. 17/634,026, 18/025,349, 18/030,225, 18/682,886, and 18/724,594, and NCT03219333 is necessarily a Fab, linked to MMAE, comprising the specific structural formula as set forth in instant claims 176, 180, 182-183, 185, 190, as evidenced by FDA, 2019 (instant PTO-892). FDA teaches that PADCEV (i.e. enfortumab vedotin-ejfv) is a nectin-4 directed ADC comprised of a fully human anti-Nectin-4 IgG1 kappa monoclonal antibody conjugated to the small molecule microtubule disrupting agent, MMAE via a protease-cleavable maleimidocaproyl valine-citrulline linker [page 11, Description]. FDA teaches that PADCEV is used in the clinical trial NCT03219333 [page 14, Clinical Studies].
Claim 201 is included in this rejection because NCT03219333 teaches that the enfortumab vedotin is administered by intravenous (IV) infusion [page 7, Arms and Interventions].
This is a provisional nonstatutory double patenting rejection.
Claims 1-2, 9, 16, 19-20, 24-25, 29, 32, 34-35, 43-44, 48, 51, 54-56, 70-71, 75, 78, 83-85, 99-100, 104, 107, 110-111, 113-115, 123-124, 128, 131-133, 141-142, 146, 149-151, 165-166, 170, 174-176, 180, 182-185, 190, 196, 201, 203-205, 210, and 214-215 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application Nos. 17/634,026, 18/025,349, 18/030,225, 18/682,886, and 18/724,594 in view of NCT03219333, 2018 (instant PTO-892), as applied to claims 1-2, 9, 170, 174-176, 180, 182-185, 190, and 201 above, and further in view of FDA, 2019 (instant PTO-892).
The teachings of copending Application Nos. 17/634,026, 18/025,349, 18/030,225, 18/682,886, 18/724,594, and NCT03219333 are above.
However, copending Application Nos. 17/634,026, 18/025,349, 18/030,225, 18/682,886, 18/724,594, and NCT03219333 do not specifically teach further determining a blood glucose level (instant claim 16), peripheral neuropathy (instant claim 29), a skin reaction (instant claim 48), a non-hematologic toxicity (instant claim 75), a hematologic toxicity (instant claim 104), fatigue (instant claim 128), and diarrhea (instant claim 146).
Regarding claims 16, 19-20, 24-25, 29, 32, 34-35, 43-44, 48, 51, 54-56, 70-71, 75, 78, 83-85, 99-100, 104, 107, 110-111, 113-115, 123-124, 128, 131-133, 141-142, 146, 149-151, 165-166, 203-205, 210, and 214-215, FDA teaches adverse reactions of PADCEV administration include hyperglycemia, peripheral neuropathy, skin reactions, nonhematologic toxicities, hematologic toxicities [pages 2-3, Dose Modifications] fatigue, and diarrhea [page 7, Clinical Trials Experience]. FDA further teaches modifying the dosage of PADCEV or permanently discontinuing PADCEV depending on the measurements and severity of the adverse reactions [pages 2-3, Dose Modifications] and dose reductions in the subjects with the adverse reactions [page 7, Clinical Trials Experience]. FDA also teaches that the recommended dose of PADCEV is 1.25 mg/kg, up to a maximum of 125 mg for patients >/= 100kg, and teaches a dose reduction schedule [page 3, Table 2].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have determined a blood glucose level (instant claim 16), peripheral neuropathy (instant claim 29), a skin reaction (instant claim 48), a non-hematologic toxicity (instant claim 75), a hematologic toxicity (instant claim 104), fatigue (instant claim 128), and diarrhea (instant claim 146), as taught by FDA, in the method of NCT03219333, copending Application Nos. 17/634,026, 18/025,349, 18/030,225, 18/682,886, 18/724,594. One would have been motivated to have determined a blood glucose level, peripheral neuropathy, a skin reaction, a non-hematologic toxicity, a hematologic toxicity, fatigue, and diarrhea in the method of administering enfortumab vedotin (PADCEV) as taught by NCT03219333 and copending Application Nos. 17/634,026, 18/025,349, 18/030,225, 18/682,886, 18/724,594, because FDA teaches that these are all adverse reactions of PADCEV administration. It further would have been obvious to have measured for these potential adverse reactions daily (as set forth in instant claims 25, 44, 71, 100, 124, 142, and 166) in order to monitor the reactions(s) possible development or progression. Additionally, it would have been obvious to have modified the dosage of PADCEV or discontinued the administration of PADCEV depending on the measurements and severity of the adverse reactions. One would have been motivated to have modified the dosage or discontinue the use of PADCEV depending on the adverse reactions because FDA teaches doing so.
Additionally, regarding the limitations of specific dosing and dosing schedules (which Applicant refers to as regimens), the art demonstrates that these are result effective variables of PADCEV and can be dependent on the adverse reactions. Through routine optimization, one of ordinary skill in the art would arrive at the specific dosing and dosing schedules as claimed in the instant claims. See MPEP 2144.05(II).
Claim 196 is included in this rejection because FDA teaches that PADCEV for injection is reconstituted in a solution containing 10 mg of the ADC, 1.4 mg histidine, 2.31 mg histidine hydrochloride monohydrate, 0.2 mg polysorbate 20, 55 mg trehalose dihydrate, with a pH of 6.0 [page 11, third paragraph].
This is a provisional nonstatutory double patenting rejection.
Examiner’s Note on Double Patenting
Efforts were made to discover any pending application or grated US patent that claimed patentably indistinct subject matter. However, it is also noted that the number of patent applications filed on this or related subject matter is significant. Applicant is in the best position to identify any other pending applications or US patents that are a) directed to the instant claimed ADC and b) discloses treatment of cancer. Assistance in identifying such documents is appreciated.
Conclusion
No claims are allowed.
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/B.E.D./Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675
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