Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Claims 25-76 are pending in the instant application.
Claims 40, 49-51, and 54 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 1/25/2026.
Restriction Response
Applicant argued with the Examiner's characterization of labels recited in claims 56 and 57 as a distinct group of species of D. Applicant argued claims 56 and 57 expressly recite that portion A (i.e., the antibody or antigen-binding fragment portion) of the ADC with Formula (I) can be an antibody or antigen-binding fragment with various labels for the detection of the antibody or antigen-binding fragment. Applicant argued, thus, unlike alleged by the Examiner, the detectable labels listed in Group (l)(ii) are not individual species of portion D (i.e., bioactive molecule) of the recited antibody-drug conjugates.
Upon further review and Applicant’s persuasive response filed 1/25/2026, instant claims 56 and 57 recite an antibody or antigen-binding fragment that has label and/or detectable label that is not required to be D. Thus, the species of ii) a detectable label, wherein individual species are further selected from enzymes peroxidase, radionuclides, fluorescent dyes, luminescent substances or biotin is withdrawn. The species of a linker and D is still valid.
The withdrawn species of 40, 49-51, and 54 do not include the subject matter of the traverse argument. The species of D comprising individual distinct species of D are still deemed separate species in claims 25-76.
The requirement is still deemed proper and is therefore made FINAL.
Applicant elected the species:
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Claims 25-39, 41-48, 52-53, and 55-76 are pending on the Applicant elected species.
Upon further search the Examiner has further included the species wherein the (D-L) is:
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Claims 25-37 and 56-67 are pending on the Examiner elected species.
Priority
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C.119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and
41.202(e).
Failure to provide a certified translation may result in no benefit being accorded
for the non-English application. The effective priority date is the filing date of
PCT/CN2021/093348 filed on 5/12/2021 in the absence of a certified translation of
CN202010410633.5 filed on 5/15/2020.
Objections to the Claims
Claims 25-39, 41-48, 52-53, and 55-68 are objected to because of the following informalities:
Regarding instant claims 25-39, 41-48, 52-53, and 55-68, “CLDN 18.2” contains a space and is inconsistent with the recitation of “CLDN18.2” in other locations of the claim set that do not contain a space. “CLDN 18.2” is present in claim 25 in option (1-2) and (2-2) and claim 67 line 1. Claims 25-39, 41-48, 52-53, and 55-68 further contain the rejected subject matter and are also rejected.
Appropriate correction is required.
Claim Rejections – 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 27, 31, 39, 41-48, 52, 66, and 72-76 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding instant claim 27, the claim claims a CH “variant” and/or a CL “variant” but the meets and bounds of “variant” are unclear to: A) what applicant intends as the scope of the “variant” ; and B) a person having ordinary skill in the art for the scope of the “variant”. For A) and B) it is unclear the number of amino acid substitutions, deletions or additions that would demarcate a “variant” from a non-variant for any CH or CL.
MPEP 2171 states Two separate requirements are set forth in 35 U.S.C. 112(b) and pre-AIA 35 U.S.C. 112, second paragraph, namely that:
(A) the claims must set forth the subject matter that the inventor or a joint inventor regards as the invention; and
(B) the claims must particularly point out and distinctly define the metes and bounds of the subject matter to be protected by the patent grant.
The first requirement is a subjective one because it is dependent on what the inventor or a joint inventor for a patent regards as his or her invention. Note that although pre-AIA 35 U.S.C. 112, second paragraph, uses the phrase "which applicant regards as his invention," pre-AIA 37 CFR 1.41(a) provides that a patent is applied for in the name or names of the actual inventor or inventors.
The second requirement is an objective one because it is not dependent on the views of the inventor or any particular individual, but is evaluated in the context of whether the claim is definite — i.e., whether the scope of the claim is clear to a hypothetical person possessing the ordinary level of skill in the pertinent art.
Regarding instant claim 39,
L1 is recited as comprising x2 as 0, 1, 2, 3, 4, 5 or 6. This is indefinite because is it unclear whether the four unpaired electrons of benzene ring are conjugated to a substituent for a selection of R1 as hydrogen and x2 less than 4 because x2 without 4 substituents would have unpaired electrons and hydrogen. Further, x2 more than 4 would require conjugation to more than 4 available unpaired electrons;
L4 is recited as comprising α as 0, 1, 2, 3, 4, 5 or 6. This is indefinite because the metes and bounds of the connection of the Z2 C3-8 cycloalkylene and the carbon triple bond is unclear wherein more than one cycloalkylene is present for α >1. It is unclear whether the attachment can be to the first cycloalkylene in a stacked cycloalkylene of α >1.
E is recited as comprising β as 0, 1, 2, 3, 4, 5 or 6. This is indefinite because is it unclear whether the four unpaired electrons of pyrimidine ring are conjugated to a substituent for a selection of R4 as hydrogen and β less than 2 because β without 2 substituents would have unpaired electrons and hydrogen. Further, β more than 2 would require conjugation to more than 4 available unpaired electrons;
Claims 41-48, and 52 are dependent on claim 39 without narrowing the scope beyond the unclear subject matter.
Regarding claim 31, the claim recites wherein CH is an IgG heavy chain constant region, “such as” an IgG1, IgG2, IgG3 or IgG4 heavy chain constant region. The IgG variants are exemplary claim language and it is unclear whether the variants are not limiting, or further limitations of the scope of the claim.
Regarding instant claim 66, the content of the parentheses of (such as NSCLC) in line 3 does not define or equate to the preceding terminology and thus is exemplary claim language which is unclear. Thus, the claim is indefinite and the metes and bounds are unclear.
Regarding instant claims 72-76, DAR has not been previously defined in a dependent claim. Thus, the claim is indefinite. The definition for DAR is present in instant claim 58.
Claims 73-76 recites the limitation "DAR" in line 1. There is insufficient antecedent basis for this limitation in the claim.
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 25-34, 36-39, 41-48, 52-53, and 55-68 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.
Regarding claim 25, the specification does not have support for an antibody or antigen-binding fragment in an ADC comprising formula (I) that comprises only a VH or VL with a defined CDR that possesses the recited function of binding human CLDN18.2. The specification and prior art do not describe a genus of known species that allow for predictable binding of the recited function of binding human CLDN18.2 or antibody secretion with less than 6 defined CDRs. Claims 26-34, 37-39, 41-48, 52-53, and 55-68 depend on claim 25 without narrowing the scope outside of the rejection;
Regarding claim 25, the specification does not have support for an antibody or antigen-binding fragment in an ADC comprising formula (I) that comprises one or more mutations to the VH or VL defined CDR that possesses the recited function of binding human CLDN18.2 or antibody secretion. Claims 26-34, 36-39, 41-48, 52-53, and 55-68 depend on claim 25 without narrowing the scope outside of the rejection;
Regarding claim 62, the specification does not have support for a method of preventing a tumor by administering a sequence defined ADC that binds human CLDN18.2 comprising formula (I) alone, in a composition, or in a pharmaceutical composition. Claims 63-67 depend on claim 62 without narrowing the scope outside of the rejection; and
Regarding claims 62-66, the specification does not have support for a method of preventing and/or treating a tumor, and/or delaying tumor progression, and/or reducing or inhibiting tumor recurrence in a subject by administering a sequence defined ADC that binds human CLDN18.2 comprising formula (I), wherein the tumor is not CLDN18.2 positive. Only claim 67 requires the tumor to be CLDN 18.2 positive, thus the other methods contain embodiments wherein the tumor is not CLDN 18.2 positive.
Scope of the claimed genus
Regarding claim 25, the claim encompasses antibodies or antigen-binding fragments in an ADC comprising formula (I) that specifically bind human CLDN18.2, wherein only a VH or VL is required, and the sequence defined CDRs comprising the VH and VL are only required in the alternative. Claims 26-34, 37-39, 41-48, 52-53, and 55-68 depend on claim 25 without narrowing the scope outside of the rejection;
Regarding claim 25, the claim encompasses antibodies or antigen-binding fragments in an ADC comprising formula (I) that specifically bind human CLDN18.2, wherein the sequence defined CDRs comprising the VH and/or VL can contain one or more mutations. Claims 26-34, 36-39, 41-48, 52-53, and 55-68 depend on claim 25 without narrowing the scope outside of the rejection;
Regarding claim 62, the claim encompasses a method of preventing and/or treating a tumor, and/or delaying tumor progression, and/or reducing or inhibiting tumor recurrence in a subject by administering a sequence defined ADC that binds human CLDN18.2 comprising formula (I) alone, in a composition, or in a pharmaceutical composition. Thus, the claim includes a method of tumor prevention. Claims 63-67 depend on claim 62 without narrowing the scope outside of the tumor prevention; and
Regarding claims 62-66, the claim encompasses a method of preventing and/or treating a tumor, and/or delaying tumor progression, and/or reducing or inhibiting tumor recurrence in a subject by administering a sequence defined ADC that binds human CLDN18.2 comprising formula (I) alone, in a composition, or in a pharmaceutical composition. Only claim 67 requires the tumor to be CLDN 18.2 positive, thus the other methods of claims 62-66 contain embodiments wherein the tumor is not CLDN 18.2 positive.
Summary of Species disclosed in the original specification
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
The specification identifies that CLDN18.2 antibodies IMAB362 and 2C6.9-hz21 effectively bound cells expressing human CLDN18.2 in Fig. 5-6 and effectively killed the cells. Fig. 12A-12P showed that an ADC comprising the antibody 2C6.9-hz21 was effective at killing tumors when administered to a subject, wherein the linker conjugates TL001
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and TL002
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were effective (specification page 53).
1)-2) The specification did not show an effective antibody or antigen-binding fragment in an ADC comprising formula (I) that comprises only a VH or VL with a defined CDR that possesses the recited function of binding human CLDN18.2, or with less than 6 sequence defined CDRs comprising a VH and VL.
3) The specification does not have experimental support for a method of preventing a tumor by administering a sequence defined ADC that binds human CLDN18.2 comprising formula (I) alone, in a composition, or in a pharmaceutical composition.
4) The specification does not have support for a method of preventing and/or treating a tumor, and/or delaying tumor progression, and/or reducing or inhibiting tumor recurrence in a subject by administering a sequence defined ADC that binds human CLDN18.2 comprising formula (I), wherein the tumor is not CLDN18.2 positive. Only tumors that expressed CLDN18.2 were targeted by the claimed ADC.
State of the Relevant Art
Human CLDN18.2 is highly expressed in a significant proportion of gastric and pancreatic adenocarcinomas, while normal tissue expression is limited to the epithelium of the stomach (Zhu G et al. (Scientific Reports 2019 9, Article number: 8420 1-11) abstract). WO 2020/135201 (Tian H et al. IDS reference) taught an CLDN18.2 antibody 2C6.9-hz21 comprising a heavy chain of SEQ ID NO:106 and a light chain of SEQ ID NO:107, which is identical to the instantly claimed heavy chain of SEQ ID NO:19 and light chain of 20, was effective at decreasing cancer growth when administered to a subject with of NCI-N87 tumors that expressed CLDN18.2 (Fig. 6B). ‘201 did not teach a structure activity relationship of the antibody CDRs that effectively bound human CLDN18.2 and were secreted. ‘201 did not show that CLDN18.2 antibodies comprising only a VH or VL were effective.
1-2) At the time of the filing of the instant application, it was well established in the art that the formation of an intact antigen-binding site in an antibody usually required the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three “complementarity determining regions” (“CDRs”) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro & Fransson, Frontiers in Bioscience 2008; 13:1619-33; (see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1). While affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (page 3 “The IgG Molecule, second and third paragraphs), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. E.g., id., (page 6 ending paragraph onto page 7). Chiu ML et al. (Antibodies 2019 8, 55, 1-80) taught the antigen binding of antibodies often results in conformational changes in the contact surface areas of both the antibody and the antigen (page 5, first paragraph). Thus, the prediction of CDR binding to the epitope is difficult to predict. Chiu further taught antibody modeling has been shown to be accurate for the framework region sequences, but CDR modeling requires further development and improvements (page 6, second paragraph). Prediction of the structure of HCDR3 could not be accurately produced when given the Fv structures without their CDR-H3s (page 6, second paragraph). Chiu taught the quality of antibody structure prediction, particularly regarding CDR-H3, remains inadequate, and the results of antibody–antigen docking are also disappointing (page 11, paragraph 2).
In addition to changes within the CDR altering target binding, alterations to the CDR have been shown to dramatically alter antibody secretion. Hasegawa H et al. (mAbs 2017, 9(5) 854-873) taught a pair of human IgG clones with a single amino acid substitution in the variable region was sufficient to alter the efficiency of immunoglobulin biosynthesis (page 866, last sentence left column). Hasegawa taught the 2 mAbs differed only by one amino acid in the LC's CDR1 and that despite the near-identity of their primary sequences, the parental mAb secreted copious amounts of IgG to the culture media, while the variant mAb induced RB phenotypes extensively and secreted 20-fold less IgG (page 866, right column, first paragraph). Importantly, the 2 model IgGs were by no means abnormal or defective as mAbs, but demonstrated a profound impact of a single amino acid substitution on immunoglobulin biosynthesis (page 866, right column, first paragraph). Thus, prior art do not describe a genus of known species that allow for predictable binding of the recited function of binding human CLDN18.2 or antibody secretion with less than 6 defined CDRs.
3) 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 MA et al. The Oncologist 2017; 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 D et al. Cell 2011 144(5) p646-674, 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 KW et al. Nature Reviews Cancer 2011 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).
4) WO 2020/135201 (Tian H et al. IDS reference) did not show that CLDN18.2 antibodies were effective when the cancer cell did not express CLDN18.2. ‘201 did show that cells that did not express CLDN18.2 were not bound by CLDN18.2 antibodies *Fig. 3G). Thus, treatment of cancer cells that did not express CLDN18.2 would not be targeted by a CLDN18.2 targeting ADC and would be ineffective.
Summary
1)-2) A genus of species is not present in the instant specification or prior art that would demonstrate a structure activity relationship would be known for antibody CDR residues for the recited function of binding the protein target human CLDN18.2. There is a lack of an appropriate number of species with identical or alternative amino acid residues within the CDR binding determinant region that indicate which amino acid residues: i) are essential for binding; ii) can be changed and still allow protein target binding; and iii) disrupt protein target binding. One of skill in the art would reasonably conclude that applicant was not in possession of the required genus of CDR exchanges or deletions of the CLDN18.2 antibody at the time of filing.
3) The Applicant does not have written description for a method of preventing a tumor by administering a sequence defined ADC that binds human CLDN18.2 comprising formula (I) alone, in a composition, or in a pharmaceutical composition.
4) The Applicant does not have written description for a method of preventing and/or treating a tumor, and/or delaying tumor progression, and/or reducing or inhibiting tumor recurrence in a subject by administering a sequence defined ADC that binds human CLDN18.2 comprising formula (I), wherein the tumor is not CLDN18.2 positive. Only tumors that expressed CLDN18.2 were targeted by the claimed ADC.
Claim Rejections – 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Regarding the species of:
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Claims 25-28, 30-36, 39, 41-48, 52-53, 55, 58-62, and 65-73 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2019/114666 (Cai J et al. IDS reference) and WO 2020/135201 (Tian H et al. IDS reference) and evidenced by translated WO 2019/114666 (Cai J et al.) and translated WO 2020/135201 (Tian H et al.).
’666 taught an ADC BT001021 comprising an anti-Trop2 antibody and the linker drug conjugate TL033, wherein the structure is:
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(page 99, [0676-0678]), wherein the DAR was 6.9 (page 105, [0783]).
’666 taught ADC BT001021: a) was dose-dependently effective in cancer cells expressing the Trop2 target in (page 110, [0863-0865] and Table 3); and b) was effective in a method of cancer treatment in a subject, wherein the subject was administered a pharmaceutical composition comprising the ADC BT001021 and a pharmaceutically acceptable excipient, wherein the tumor expressed Trop-2 and tumor growth was reduced (pages 112-113, [0889-0914, Tables 4-6, Figs 44-47).
‘666 did not teach: 1) an ADC wherein the antibody is an anti-CLDN18.2 antibody, but this is obvious in view of ‘201
‘201 taught a CLDN18.2 antibody 2C6.9-hz21 comprising a heavy chain of SEQ ID NO:106 and a light chain of SEQ ID NO:107 ([0447]) was effective at decreasing cancer growth when administered to a subject with of NCI-N87 gastric cancer tumors that expressed CLDN18.2 (Fig. 6B).
Regarding instant claims 25-28, 30-36, 39, 41-48, 52-53, 55, 58-62, 65-73, it would have been obvious for a person having ordinary skill in the art to take the effective method of cancer treatment in a subject, wherein the subject was administered a pharmaceutical composition comprising the ADC BT001021 and a pharmaceutically acceptable excipient, wherein the DAR of the ADC was 6.9, wherein the tumor expressed Trop-2 of ‘666 – and modify the method to: 1) exchange the tumor targeting antibody from an anti-Trop2 antibody to the tumor targeting antibody of 2C6.9-hz21 comprising a heavy chain of SEQ ID NO:106 and a light chain of SEQ ID NO:107; 2) treat gastric cancer tumors that express the target CLDN18.2.
This is obvious because: 1-2) the CLDN18.2 antibody 2C6.9-hz21 comprising a heavy chain of SEQ ID NO:106 and a light chain of SEQ ID NO:107 was effective at decreasing cancer growth when administered to a subject with of gastric cancer tumors that expressed CLDN18.2.
There is a reasonable expectation of success because the ADC BT001021 is effective at killing cancer cells and: 1-2) the CLDN18.2 antibody 2C6.9-hz21 comprising a heavy chain of SEQ ID NO:106 and a light chain of SEQ ID NO:107 was effective at decreasing cancer growth when administered to a subject with gastric cancer tumors that expressed CLDN18.2.
This would produce a method of gastric cancer tumor (instant claim 66) treatment, which is a solid tumor (instant claim 65), in a subject, wherein the subject was administered a pharmaceutical composition comprising an ADC, wherein the drug linker is
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(instant claims 39, 41-48, 52-53, and 55), wherein the antibody is 2C6.9-hz21 comprising a heavy chain of SEQ ID NO:106 and a light chain of SEQ ID NO:107, which is identical to the instantly claimed heavy chain of SEQ ID NO:19 and light chain of SEQ ID NO:20 (instant claim 36) and is further comprised of a heavy chain with instant SEQ ID NO:14 (instant claim 26), and instant SEQ ID NO:1, 21, 3 and an IgG1 CH of instant SEQ ID NO:16 (instant claims 27 and 31-32) and a light chain with instant SEQ ID NO:15, and instant SEQ ID NO:4-6 and kappa light chain CL of instant SEQ ID NO:17 (instant claims 33-34) which have human frameworks (instant claim 30), and a pharmaceutically acceptable excipient (instant claims 61 and 72 ), wherein the DAR of the ADC was 6.9 and γ is between 6-7 (instant claims 28, 58-60, and 73), wherein the tumor is positive for CLDN18.2 expression (instant claim 67) (instant claims 25, 35, 62, and 68-71).
Claims 25-28, 30-37, 39, 41-48, 52-53, 55, 58-62, and 65-73 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2019/114666 (Cai J et al. IDS reference) and WO 2020/135201 (Tian H et al. IDS reference) as applied to claims 25-28, 30-36, 39, 41-48, 52-53, 55, 58-62, and 65-73 above, and further in view of de Goeij BECG et al. (Mol Cancer Ther 2016 15 (11) 2688–2697) and evidenced by translated WO 2019/114666 (Cai J et al.).
’666 and ‘201 are described above.
’666 further taught the antibody as a bispecific antibody (page 32, [0137]).
‘666 did not teach a single embodiment of a bispecific ADC and the drug-linker structure, but this is obvious in view of ‘201 and de Goeij
de Goeij taught a bispecific ADC was effective in a method of treating cancer cells, wherein the ADC comprised a tumor specificity antibody as well as an antibody to facilitate targeting to the lysosomal compartment to enhance lysosomal ADC delivery, wherein the antibody targeted CD63 for lysosomal targeting (abstract).
Regarding instant claim 37, it would have been obvious for a person having ordinary skill in the art to take the method of ’666 and ‘201 above of a method of gastric cancer tumor treatment in a subject, wherein the subject was administered a pharmaceutical composition comprising an ADC, wherein the drug linker is
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, wherein the antibody is 2C6.9-hz21, and a pharmaceutically acceptable excipient, wherein the DAR of the ADC was 6.9, wherein the tumor is positive for CLDN18.2 expression – and exchange the antibody to include a bispecific antibody of 2C6.9-hz21 and an anti-CD63 in the ADC in view of de Goeij.
This is obvious because ‘666 taught bispecific antibodies in the ADC and: 1) de Goeij taught a bispecific ADC was effective in a method of treating cancer cells, wherein the ADC comprised a tumor specificity antibody as well as an antibody to facilitate targeting to the lysosomal compartment to enhance lysosomal ADC delivery, wherein the antibody targeted CD63 for lysosomal targeting.
There is a reasonable expectation of success because: 1) an ADC comprised of 2C6.9-hz21 and an anti-CD63 antibody would target CLDN18.2 for tumor specificity as well as CD63 to facilitate targeting to the lysosomal compartment to enhance lysosomal ADC delivery.
This would produce a method of gastric cancer tumor treatment in a subject, wherein the subject was administered a pharmaceutical composition comprising an ADC, wherein the drug linker is
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, wherein the antibody is a bispecific 2C6.9-hz21 and anti-CD63 antibody, and a pharmaceutically acceptable excipient, wherein the DAR of the ADC was 6.9, wherein the tumor is positive for CLDN18.2 expression
Claims 25-28, 30-36, 39, 41-48, 52-53, 55-62, and 65-73 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2019/114666 (Cai J et al. IDS reference) and WO 2020/135201 (Tian H et al. IDS reference) as applied to claims 25-28, 30-36, 39, 41-48, 52-53, 55, 58-62, and 65-73 above, and further in view of Xie H et al. (JPET 2004 308(3) 1073-1082).
’666 and ‘201 are described above.
‘666 did not teach a detectable label of a radionucleotide on the antibody of the ADC, but this is obvious in view of Xie.
Xie taught a radionucleotide labeled ADC, 125I- huC242-DM1, wherein administering the labeled ADC allowed blood and tissue distribution to be studied in subjects (Tables 1-2 and Figs. 1 and 6).
Regarding instant claims 56-57, it would have been obvious for a person having ordinary skill in the art to take the method of ’666 and ‘201 above of a method of gastric cancer tumor treatment in a subject, wherein the subject was administered a pharmaceutical composition comprising an ADC, wherein the drug linker is
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, wherein the antibody is 2C6.9-hz21, and a pharmaceutically acceptable excipient, wherein the DAR of the ADC was 6.9, wherein the tumor is positive for CLDN18.2 expression – and further include a 125I radionucleotide on the antibody of the ADC in view of Xie.
This is obvious with a reasonable expectation of success because: 1a) Xie taught a radionucleotide labeled ADC, 125I- huC242-DM1, wherein administering the labeled ADC allowed blood and tissue distribution to be studied in subjects. Thus, radiolabeling 2C6.9-hz21 with 125I would allow the blood and tissue distribution to be determined for the ADC for pharmacokinetic determination.
This would produce a method of gastric cancer tumor treatment in a subject, wherein the subject was administered a pharmaceutical composition comprising an ADC, wherein the drug linker is
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, wherein the antibody is 125I-2C6.9-hz21, wherein 125I is a detectable radionucleotide (instant claims 56-57) and a pharmaceutically acceptable excipient, wherein the DAR of the ADC was 6.9, wherein the tumor is positive for CLDN18.2 expression.
Claims 25-28, 30-36, 39, 41-48, 52-53, 55, and 58-73 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2019/114666 (Cai J et al. IDS reference) and WO 2020/135201 (Tian H et al. IDS reference) as applied to claims 25-28, 30-36, 39, 41-48, 52-53, 55, 58-62, and 65-73 above, and further in view of Bailly C et al. (NAR Cancer 2020 2(1) 1-20).
’666 and ‘201 are described above.
‘666 did not teach combination therapy with an immune checkpoint inhibitor, but this is obvious in view of ‘201 and Bailly
Bailly taught an effective combination treatment for cancer comprising: a) an immunotherapy checkpoint inhibitor anti-PD-1 antibody; and b) trastuzumab deruxtecan (DS-8201a), which comprises an HER2-targeting antibody with a camptothecin derivative, wherein the combination was more effective than either monotherapy, and wherein through its topoisomerase 1-targeted payload, this ADC enhances antitumor immunity and upregulates PD-L1 expression (page 10, left column to right column, bridging paragraph). Bailly taught topoisomerase inhibitors that are camptothecins are known to combine well with immunotherapy, wherein immune-modulating functions of a topoisomerase 1 inhibitor leads to a supra-additive effect when administered in combination with anti-PD-L1-blocking antibodies (page 10, left column, second to last paragraph)
Regarding instant claims 63-64, it would have been obvious for a person having ordinary skill in the art to take the method of ’666 and ‘201 above of a method of gastric cancer tumor treatment in a subject, wherein the subject was administered a pharmaceutical composition comprising an ADC, wherein the drug linker is
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, wherein the antibody is 2C6.9-hz21, and a pharmaceutically acceptable excipient, wherein the DAR of the ADC was 6.9, wherein the tumor is positive for CLDN18.2 expression – and further include an immune checkpoint inhibitor anti-PD-1 antibody in the pharmaceutical composition in view of Bailly.
This is obvious with a reasonable expectation of success because: 1a) Bailly taught an effective combination treatment for cancer comprising: a) an immunotherapy checkpoint inhibitor anti-PD-1 antibody; and b) trastuzumab deruxtecan (DS-8201a), which comprises an HER2-targeting antibody with a camptothecin derivative, wherein the combination was more effective than either monotherapy, and wherein through its topoisomerase 1-targeted payload, this ADC enhances antitumor immunity and upregulates PD-L1 expression. 1b) Bailly taught topoisomerase inhibitors that are camptothecins are known to combine well with immunotherapy, wherein immune-modulating functions of a topoisomerase 1 inhibitor leads to a supra-additive effect when administered in combination with immune checkpoint blocking antibodies. Thus, combination with an immune checkpoint inhibitor and an ADC comprising a camptothecin derivative would be expected to be effective.
This would produce a method of gastric cancer tumor treatment in a subject, wherein the subject was administered a pharmaceutical composition comprising an ADC, wherein the drug linker is
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, wherein the antibody is 2C6.9-hz21, an anti-PD-1 immune checkpoint inhibitor (instant claims 63-64) and a pharmaceutically acceptable excipient, wherein the DAR of the ADC was 6.9, wherein the tumor is positive for CLDN18.2 expression.
Claims 25-28, 30-36, 39, 41-48, 52-53, 55, 58-62, and 65-76 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2019/114666 (Cai J et al. IDS reference) and WO 2020/135201 (Tian H et al. IDS reference) as applied to claims 25-28, 30-36, 39, 41-48, 52-53, 55, 58-62, and 65-73 above, and further in view of Goulet DR et al. (Journal of Pharm Sci 2020 109(1) 74-103) and evidenced by translated WO 2019/114666 (Cai J et al.).
’666 and ‘201 are described above.
’666 further taught the antibody DAR as 5-8 (page 41, [0174]).
‘666 did not teach a single embodiment of an ADC with a DAR of about 3.8, 7.1, or 7.4, but this is obvious in view of Goulet.
Goulet taught a straightforward conjugation strategy, used for brentuximab vedotin, is conjugation to reduced interchain cysteines, wherein there are 8 interchain cysteines per IgG, and wherein heterogeneity of conjugation occurs (pages 90-91, bridging paragraph). Goulet taught conjugation via native amino acids has produced several efficacious ADCs (pages 90-91, bridging paragraph). Thus, a DAR of between 1 and 8 is able to be obtained via drug-linker conjugation to cysteine residues.
Regarding instant claims 74-76, it would have been obvious for a person having ordinary skill in the art to take the method of ’666 and ‘201 above of a method of gastric cancer tumor treatment in a subject, wherein the subject was administered a pharmaceutical composition comprising an ADC, wherein the drug linker is
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, wherein the antibody is 2C6.9-hz21, and a pharmaceutically acceptable excipient, wherein the DAR of the ADC was 6.9, wherein the tumor is positive for CLDN18.2 expression – and include a DAR between 5-8 or between 1-8 in the ADC in view of ‘666 or Goulet.
This is obvious because ‘666 taught a DAR of between 5-8 and: 1) Goulet taught a straightforward conjugation strategy, used for brentuximab vedotin, is conjugation to reduced interchain cysteines, wherein there are 8 interchain cysteines per IgG, and wherein heterogeneity of conjugation occurs. Thus, a γ and DAR of between 1 and 8 is able to be obtained via drug-linker conjugation to cysteine residues.
There is a reasonable expectation of success because the cancer cytotoxic linker drug is known to be effective to cancer cells when attached to a cancer targeted antibody and would be expected to be effective for ADC DAR values between 1 and 8; and 1) Goulet taught conjugation via native amino acids has produced several efficacious ADCs.
This would produce a method of gastric cancer tumor treatment in a subject, wherein the subject was administered a pharmaceutical composition comprising an ADC, wherein the drug linker is
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, wherein the antibody is 2C6.9-hz21 and a pharmaceutically acceptable excipient, wherein the DAR of the ADC is between 1 and 8 (instant claims 74-76), wherein the tumor is positive for CLDN18.2 expression.
Regarding the species
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Claims 25-28, 30-36, 58-62, and 65-67 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2014/092804 (Govindan SV et al.) and WO 2020/135201 (Tian H et al. IDS reference).
‘804 taught an effective method of treating pancreatic cancer that expressed EGP-1, comprising administering a pharmaceutical composition comprising of the ADC hRS7-CL2A-SN-38 (page 89, [0232] and Fig. 2) and a pharmaceutically acceptable excipient, wherein the antibody was conjugated to the CLA2A-SN-38 linker of
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(page 85 and pages 87-88 [0231]), wherein hRS7-CL2A-SN-38 had a DAR of 5.8 (page 88, Table 7, [0231]).
‘804 did not teach: 1) an ADC wherein the antibody is an anti-CLDN18.2 antibody, but this is obvious in view of ‘201
‘201 taught a CLDN18.2 antibody 2C6.9-hz21 comprising a heavy chain of SEQ ID NO:106 and a light chain of SEQ ID NO:107 ([0447]) was effective at decreasing cancer growth when administered to a subject with of NCI-N87 gastric cancer tumors that expressed CLDN18.2 (Fig. 6B).
Regarding instant claims 25-28, 30-36, 58-62, and 65-67, it would have been obvious for a person having ordinary skill in the art to take the effective method of pancreatic cancer treatment in a subject, comprising administering a pharmaceutical composition comprising of the ADC hRS7-CL2A-SN-38 and a pharmaceutically acceptable excipient, wherein the antibody was conjugated to the CLA2A-SN-38 linker of
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, wherein hRS7-CL2A-SN-38 had a DAR of 5.8 and γ is between 5-6, wherein the tumor expressed EGP-1 of ’804 – and modify the method to:
1) exchange the tumor targeting antibody from an anti-EGP-1 antibody to the tumor targeting antibody of 2C6.9-hz21 comprising a heavy chain of SEQ ID NO:106 and a light chain of SEQ ID NO:107; 2) treat gastric cancer tumors that express the target CLDN18.2.
This is obvious because: 1-2) the CLDN18.2 antibody 2C6.9-hz21 comprising a heavy chain of SEQ ID NO:106 and a light chain of SEQ ID NO:107 was effective at decreasing cancer growth when administered to a subject with of gastric cancer tumors that expressed CLDN18.2.
There is a reasonable expectation of success because the ADC hRS7-CL2A-SN-38 is effective at killing cancer cells and: 1-2) the CLDN18.2 antibody 2C6.9-hz21 comprising a heavy chain of SEQ ID NO:106 and a light chain of SEQ ID NO:107 was effective at decreasing cancer growth when administered to a subject with gastric cancer tumors that expressed CLDN18.2.
This would produce a method of gastric cancer tumor (instant claim 66) treatment, which is a solid tumor (instant claim 65), in a subject, wherein the subject was administered a pharmaceutical composition comprising an ADC, wherein the drug linker is
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, wherein the antibody is 2C6.9-hz21 comprising a heavy chain of SEQ ID NO:106 and a light chain of SEQ ID NO:107, which is identical to the instantly claimed heavy chain of SEQ ID NO:19 and light chain of SEQ ID NO:20 (instant claim 36 ) and is further comprised of a heavy chain with instant SEQ ID NO:14 (instant claim 26), and instant SEQ ID NO:1, 21, 3 and an IgG1 CH of instant SEQ ID NO:16 (instant claims 27 and 31-32) and a light chain with instant SEQ ID NO:15, and instant SEQ ID NO:4-6 and kappa light chain CL of instant SEQ ID NO:17 (instant claims 33-34 ) which have human frameworks (instant claim 30), and a pharmaceutically acceptable excipient (instant claim 61), wherein the DAR and γ is between 5-6 of the ADC was 5.8 (instant claims 28 and 58-60), wherein the tumor is positive for CLDN18.2 expression (instant claim 67) (instant claims 25, 35, and 62).
Claims 25-28, 30-37, 58-62, and 65-67 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2014/092804 (Govindan SV et al.) and WO 2020/135201 (Tian H et al. IDS reference) as applied to claims 25-28, 30-36, 58-62, and 65-67 above, and further in view of de Goeij BECG et al. (Mol Cancer Ther 2016 15 (11) 2688–2697).
’804 and ‘201 are described above.
’804 further taught the antibody as a bispecific antibody (page 4, [09]).
’804 did not teach a single embodiment of a bispecific ADC and the drug-linker structure, but this is obvious in view of ‘201 and de Goeij
de Goeij taught a bispecific ADC was effective in a method of treating cancer cells, wherein the ADC comprised a tumor specificity antibody as well as an antibody to facilitate targeting to the lysosomal compartment to enhance lysosomal ADC delivery, wherein the antibody targeted CD63 for lysosomal targeting (abstract).
Regarding instant claim 37, it would have been obvious for a person having ordinary skill in the art to take the method of ’804 and ‘201 above of a method of gastric cancer tumor treatment in a subject, wherein the subject was administered a pharmaceutical composition comprising an ADC, wherein the drug linker is
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, wherein the antibody is 2C6.9-hz21, and a pharmaceutically acceptable excipient, wherein the DAR of the ADC was 5.8, wherein the tumor is positive for CLDN18.2 expression – and exchange the antibody to include a bispecific antibody of 2C6.9-hz21 and an anti-CD63 in the ADC in view of de Goeij.
This is obvious because ‘804 taught bispecific antibodies in the ADC and: 1) de Goeij taught a bispecific ADC was effective in a method of treating cancer cells, wherein the ADC comprised a tumor specificity antibody as well as an antibody to facilitate targeting to the lysosomal compartment to enhance lysosomal ADC delivery, wherein the antibody targeted CD63 for lysosomal targeting.
There is a reasonable expectation of success because: 1) an ADC comprised of 2C6.9-hz21 and an anti-CD63 antibody would target CLDN18.2 for tumor specificity as well as CD63 to facilitate targeting to the lysosomal compartment to enhance lysosomal ADC delivery.
This would produce a method of gastric cancer tumor treatment in a subject, wherein the subject was administered a pharmaceutical composition comprising an ADC, wherein the drug linker is
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, wherein the antibody is a bispecific 2C6.9-hz21 and anti-CD63 antibody, and a pharmaceutically acceptable excipient, wherein the DAR of the ADC was 5.8, wherein the tumor is positive for CLDN18.2 expression
Claims 25-28, 30-36, 56-62, and 65-67 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2014/092804 (Govindan SV et al.) and WO 2020/135201 (Tian H et al. IDS reference) as applied to claims 25-28, 30-36, 58-62, and 65-67 above, and further in view of Xie H et al. (JPET 2004 308(3) 1073-1082).
’804 and ‘201 are described above.
‘804 did not teach a detectable label of a radionucleotide on the antibody of the ADC, but this is obvious in view of Xie.
Xie taught a radionucleotide labeled ADC, 125I- huC242-DM1, wherein administering the labeled ADC allowed blood and tissue distribution to be studied in subjects (Tables 1-2 and Figs. 1 and 6).
Regarding instant claims 56-57, it would have been obvious for a person having ordinary skill in the art to take the method of ’804 and ‘201 above of a method of gastric cancer tumor treatment in a subject, wherein the subject was administered a pharmaceutical composition comprising an ADC, wherein the drug linker is
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, wherein the antibody is 2C6.9-hz21, and a pharmaceutically acceptable excipient, wherein the DAR of the ADC was 5.8, wherein the tumor is positive for CLDN18.2 expression – and further include a 125I radionucleotide on the antibody of the ADC in view of Xie.
This is obvious with a reasonable expectation of success because: 1a) Xie taught a radionucleotide labeled ADC, 125I- huC242-DM1, wherein administering the labeled ADC allowed blood and tissue distribution to be studied in subjects. Thus, radiolabeling 2C6.9-hz21 with 125I would allow the blood and tissue distribution to be determined for the ADC for pharmacokinetic determination.
This would produce a method of gastric cancer tumor treatment in a subject, wherein the subject was administered a pharmaceutical composition comprising an ADC, wherein the drug linker is
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, wherein the antibody is 125I-2C6.9-hz21, wherein 125I is a detectable radionucleotide (instant claims 56-57) and a pharmaceutically acceptable excipient, wherein the DAR of the ADC was 5.8, wherein the tumor is positive for CLDN18.2 expression.
Claims 25-28, 30-36, 58-64, and 65-67 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2014/092804 (Govindan SV et al.) and WO 2020/135201 (Tian H et al. IDS reference) as applied to claims 25-28, 30-36, 58-62, and 65-67 above, and further in view of Bailly C et al. (NAR Cancer 2020 2(1) 1-20).
’804 and ‘201 are described above.
‘804 did not teach combination therapy with an immune checkpoint inhibitor, but this is obvious in view of ‘201 and Bailly
Bailly taught an effective combination treatment for cancer comprising: a) an immunotherapy checkpoint inhibitor anti-PD-1 antibody; and b) trastuzumab deruxtecan (DS-8201a), which comprises an HER2-targeting antibody with a camptothecin derivative, wherein the combination was more effective than either monotherapy, and wherein through its topoisomerase 1-targeted payload, this ADC enhances antitumor immunity and upregulates PD-L1 expression (page 10, left column to right column, bridging paragraph). Bailly taught topoisomerase inhibitors that are camptothecins are known to combine well with immunotherapy, wherein immune-modulating functions of a topoisomerase 1 inhibitor leads to a supra-additive effect when administered in combination with anti-PD-L1-blocking antibodies (page 10, left column, second to last paragraph)
Regarding instant claims 63-64, it would have been obvious for a person having ordinary skill in the art to take the method of ’804 and ‘201 above of a method of gastric cancer tumor treatment in a subject, wherein the subject was administered a pharmaceutical composition comprising an ADC, wherein the drug linker is
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, wherein the antibody is 2C6.9-hz21, and a pharmaceutically acceptable excipient, wherein the DAR of the ADC was 5.8, wherein the tumor is positive for CLDN18.2 expression – and further include an immune checkpoint inhibitor anti-PD-1 antibody in the pharmaceutical composition in view of Bailly.
This is obvious with a reasonable expectation of success because: 1a) Bailly taught an effective combination treatment for cancer comprising: a) an immunotherapy checkpoint inhibitor anti-PD-1 antibody; and b) trastuzumab deruxtecan (DS-8201a), which comprises an HER2-targeting antibody with a camptothecin derivative, wherein the combination was more effective than either monotherapy, and wherein through its topoisomerase 1-targeted payload, this ADC enhances antitumor immunity and upregulates PD-L1 expression. 1b) Bailly taught topoisomerase inhibitors that are camptothecins are known to combine well with immunotherapy, wherein immune-modulating functions of a topoisomerase 1 inhibitor leads to a supra-additive effect when administered in combination with immune checkpoint blocking antibodies. Thus, combination with an immune checkpoint inhibitor and an ADC comprising a camptothecin derivative would be expected to be effective.
This would produce a method of gastric cancer tumor treatment in a subject, wherein the subject was administered a pharmaceutical composition comprising an ADC, wherein the drug linker is
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, wherein the antibody is 2C6.9-hz21, an anti-PD-1 immune checkpoint inhibitor (instant claims 63-64) and a pharmaceutically acceptable excipient, wherein the DAR of the ADC was 5.8, wherein the tumor is positive for CLDN18.2 expression.
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.
Regarding the species of:
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Claims 25-28, 30-37, 39, 41-48, 52-53, and 58-73 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-43 of U.S. Patent No. 12,297,265 in view of WO 2019/114666 (Cai J et al. IDS reference) and evidenced by translated WO 2019/114666 (Cai J et al.).
‘265 taught antibody or antigen-binding fragment thereof that specifically bind to CLDN18.2 in patented claims 1-11, wherein the antibody comprises a VH of SEQ ID NO:40 and a VL of SEQ ID NO:41 in patented claim 1 and:
further comprises a heavy chain constant region (CH) having a sequence as set forth in SEQ ID NO: 42 and a light chain constant region (CL) having a sequence as set forth in SEQ ID NO: 43 in patented claim 23;
wherein the VH and/or VL of the antibody or antigen binding fragment thereof comprises Framework Regions (FR) derived from a human or a mouse immunoglobulin in patented claim 28;
in a conjugate in patent claim 12;
in a multispecific antibody in claim 14;
in a pharmaceutical composition which comprises a pharmaceutically acceptable carrier and/or an excipient in patented claim 15;
in a pharmaceutical composition according which further comprises a second antibody that specifically binds to PD-1 in patented claim 16;
is in a method for treating a tumor in a subject, wherein the tumor is CLDN18.2 positive, the method comprising administering to the subject in need thereof an effective amount of the pharmaceutical composition of claim 15, which further comprises administering an immunotherapy in patented claim 18-19;
wherein the tumor is a solid tumor of gastric cancer in patented claims 20 and 22,
The claims of ‘265 did not teach: 1) a conjugate wherein the linker drug is
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, but this is obvious in view of ‘666.
’666 taught an ADC BT001021 comprising an anti-Trop2 antibody and the linker drug conjugate TL033, wherein the structure is:
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(page 99, [0676-0678]), wherein the DAR was 6.9 (page 105, [0783]).
’666 taught ADC BT001021: a) was dose-dependently effective in cancer cells expressing the Trop2 target in (page 110, [0863-0865] and Table 3); and b) was effective in a method of cancer treatment in a subject, wherein the subject was administered a pharmaceutical composition comprising the ADC BT001021 and a pharmaceutically acceptable excipient, wherein the tumor expressed Trop-2 and tumor growth was reduced (pages 112-113, [0889-0914, Tables 4-6, Figs 44-47).
Regarding instant claims 25-28, 30-37, 39, 41-48, 52-53, and 58-73, it would have been obvious for a person having ordinary skill in the art to take ‘265 patented claims 1, 12, 14-16, 18-20, 22-23, and 28 of a method for treating a gastric tumor in a subject, wherein the tumor is CLDN18.2 positive, the method comprising administering to the subject in need thereof an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a multispecific conjugate, wherein the antibody comprises a VH of ‘265 SEQ ID NO:40 and a VL of ‘265 SEQ ID NO:41 and a CH of ‘265 SEQ ID NO: 42 and a CL of ‘265 SEQ ID NO: 43, with human framework sequences, in combination a second antibody that specifically binds to PD-1 as an immunotherapy – and modify the method by: 1) including
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as the conjugate with a DAR of 6.9 in view of ‘666.
This is obvious because: 1) ‘666 taught an ADC BT001021 comprising an anti-Trop2 antibody and the linker drug conjugate TL033, wherein the structure is:
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, wherein the DAR was 6.9, wherein ADC BT001021: a) was dose-dependently effective in cancer cells expressing the Trop2 target; and b) was effective in a method of cancer treatment in a subject, wherein the subject was administered a pharmaceutical composition comprising the ADC BT001021 and a pharmaceutically acceptable excipient, wherein the tumor expressed Trop-2 and tumor growth was reduced.
There is a reasonable expectation of success because the claims of ‘265 taught the CLDN18.2 antibody was useful in a method of treating cancer and as a conjugate bound to a cytotoxin and: 1) the linker drug
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was effective against cancer cells.
This would produce a method for treating a gastric cancer (instant claims 56-57 and 66), which is a solid tumor (instant claim 65), in a subject, wherein the tumor is CLDN18.2 positive (instant claim 67), the method comprising administering to the subject in need thereof an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier (instant claims 61 and 72) and a multispecific (instant claim 37) conjugate, wherein the structure is:
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(instant claims 39, 41-48, 52-53, and 55), wherein the antibody comprises a VH of ‘265 SEQ ID NO:40 and a VL of ‘265 SEQ ID NO:41 and a CH of ‘265 SEQ ID NO: 42 and a CL of ‘265 SEQ ID NO: 43, which is identical to the instantly claimed heavy chain of SEQ ID NO:19 and light chain of SEQ ID NO:20 (instant claim 36) and is further comprised of a heavy chain with instant SEQ ID NO:14 (instant claim 26), and instant SEQ ID NO:1, 21, 3 and an IgG1 CH of instant SEQ ID NO:16 (instant claims 27 and 31-32) and a light chain with instant SEQ ID NO:15, and instant SEQ ID NO:4-6 and kappa light chain CL of instant SEQ ID NO:17 (instant claims 33-34) which have human frameworks (instant claim 30), wherein the DAR is 6.9 and γ is between 6-7 (instant claims 28, 58-60, and 73), in combination a second antibody that specifically binds to PD-1 as an immunotherapy (instant claim 63-64) (instant claims 25, 35, 62, and 68-71).
Claims 25-28, 30-37, 39, 41-48, 52-53, and 58-76 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-43 of U.S. Patent No. 12,297,265 in view of WO 2019/114666 (Cai J et al. IDS reference) and Goulet DR et al. (Journal of Pharm Sci 2020 109(1) 74-103) and evidenced by translated WO 2019/114666 (Cai J et al.).
The claims of the ‘265 patent in view of ‘666 teach the limitations of claims 25-28, 30-37, 39, 41-48, 52-53, and 58-73 for the reasons set forth above.
‘265 and ‘666 are described above.
’666 further taught the antibody DAR as 5-8 (page 41, [0174]).
The claims of ‘265 did not teach a single embodiment of an ADC with a DAR of about 3.8, 7.1, or 7.4, but this is obvious in view of Goulet.
Goulet taught a straightforward conjugation strategy, used for brentuximab vedotin, is conjugation to reduced interchain cysteines, wherein there are 8 interchain cysteines per IgG, and wherein heterogeneity of conjugation occurs (pages 90-91, bridging paragraph). Goulet taught conjugation via native amino acids has produced several efficacious ADCs (pages 90-91, bridging paragraph). Thus, a DAR of between 1 and 8 is able to be obtained via drug-linker conjugation to cysteine residues.
Regarding instant claims 74-76, it would have been obvious for a person having ordinary skill in the art to take the method of ‘265 and ’666 above – and include a DAR between 5-8 or between 1-8 in the ADC in view of ‘666 and Goulet.
This is obvious because ‘666 taught a DAR of between 5-8 and: 1) Goulet taught a straightforward conjugation strategy, used for brentuximab vedotin, is conjugation to reduced interchain cysteines, wherein there are 8 interchain cysteines per IgG, and wherein heterogeneity of conjugation occurs. Thus, a γ and DAR of between 1 and 8 is able to be obtained via drug-linker conjugation to cysteine residues.
There is a reasonable expectation of success because the cancer cytotoxic linker drug is known to be effective to cancer cells when attached to a cancer targeted antibody and would be expected to be effective for ADC DAR values between 1 and 8; and 1) Goulet taught conjugation via native amino acids has produced several efficacious ADCs.
Claims 25-26, 28, 30, 35, 37, 39, 41-48, 52-53, and 58-70 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12, 15-16, 18, 21-25 of copending Application No. 18/000,174 in view of WO 2019/114666 (Cai J et al. IDS reference) and evidenced by translated WO 2019/114666 (Cai J et al.).
‘174 taught a bispecific antibody comprising an antibody that binds to CLDN18.2 in copending claims 1-12 15-16, 18, 21-25. ‘174 taught a bispecific antibody comprising an antibody that binds to CLDN18.2, wherein the antibody comprises a VH of SEQ ID NO:6 and a VL of SEQ ID NO:3 copending claim 1, a pharmaceutical composition comprising the bispecific antibody as a conjugate linked to a cytotoxin and a pharmaceutically acceptable carrier in copending claims 18 and 22, a method for treating pancreatic cancer comprising administering to a subject in need thereof the bispecific antibody in copending claim 21.
The claims of ‘174 did not teach: 1) a conjugate wherein the linker drug is
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, but this is obvious in view of ‘666.
’666 taught an ADC BT001021 comprising an anti-Trop2 antibody and the linker drug conjugate TL033, wherein the structure is:
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(page 99, [0676-0678]), wherein the DAR was 6.9 (page 105, [0783]).
’666 taught ADC BT001021: a) was dose-dependently effective in cancer cells expressing the Trop2 target in (page 110, [0863-0865] and Table 3); and b) was effective in a method of cancer treatment in a subject, wherein the subject was administered a pharmaceutical composition comprising the ADC BT001021 and a pharmaceutically acceptable excipient, wherein the tumor expressed Trop-2 and tumor growth was reduced (pages 112-113, [0889-0914, Tables 4-6, Figs 44-47).
Regarding instant claims 25-26, 28, 30, 35, 37, 39, 41-48, 52-53, and 58-70, and 72-73, it would have been obvious for a person having ordinary skill in the art to take ‘174 patented claims 1, 18, 21-22 of a method for treating a pancreatic cancer in a subject, the method comprising administering to the subject in need thereof an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a bispecific cytotoxin conjugate, wherein the antibody comprises a VH of ‘174 SEQ ID NO:6 and a VL of ‘174 SEQ ID NO:3, with human framework sequences – and modify the method by:
1) including
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as the conjugate with a DAR of 6.9 in view of ‘666; and 2) treating a cancer that is CLDN18.2 positive.
This is obvious because: 1) ‘666 taught an ADC BT001021 comprising an anti-Trop2 antibody and the linker drug conjugate TL033, wherein the structure is:
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, wherein the DAR was 6.9, wherein ADC BT001021: a) was dose-dependently effective in cancer cells expressing the Trop2 target; and b) was effective in a method of cancer treatment in a subject, wherein the subject was administered a pharmaceutical composition comprising the ADC BT001021 and a pharmaceutically acceptable excipient, wherein the tumor expressed Trop-2 and tumor growth was reduced; and 2) CLDN18.2 is the target of the claimed antibody and thus the ADC would target the cancer cells expressing the CLDN18.2 target.
There is a reasonable expectation of success because the claims of ‘265 taught the CLDN18.2 antibody was useful in a method of treating cancer and as a conjugate bound to a cytotoxin and: 1) the linker drug
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was effective against cancer cells; and 2) CLDN18.2 is the target of the claimed antibody and thus the ADC would target the cancer cells expressing the CLDN18.2 target.
This would produce a method for treating a pancreatic cancer (instant claims 56-57 and 66), which is a solid tumor (instant claim 65), in a subject, wherein the tumor is CLDN18.2 positive (instant claim 67), the method comprising administering to the subject in need thereof an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier (instant claims 61 and 72) and a bispecific (instant claim 37) conjugate, wherein the structure is:
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(instant claims 39, 41-48, 52-53, and 55), wherein the antibody comprises a VH of ‘174 SEQ ID NO:6 and a VL of ‘174 SEQ ID NO:3, which is identical to a VH of instant SEQ ID NO:14 (instant claim 26), and instant SEQ ID NO:1, 21, 3 and a VL with instant SEQ ID NO:15, and instant SEQ ID NO:4-6 with human framework sequences (instant claim 30), wherein the DAR is 6.9 and γ is between 6-7 (instant claims 28, 58-60, and 73), in combination a second antibody that specifically binds to PD-1 as an immunotherapy (instant claim 63-64) (instant claims 25, 35, 62, and 68-70).
This is a provisional nonstatutory double patenting rejection.
Regarding the species
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Claims 25-28, 30-37, and 56-67 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-43 of U.S. Patent No. 12,297,265 in view of WO 2014/092804 (Govindan SV et al.).
‘265 taught antibody or antigen-binding fragment thereof that specifically bind to CLDN18.2 in patented claims 1-11, wherein the antibody comprises a VH of SEQ ID NO:40 and a VL of SEQ ID NO:41 in patented claim 1 and:
further comprises a heavy chain constant region (CH) having a sequence as set forth in SEQ ID NO: 42 and a light chain constant region (CL) having a sequence as set forth in SEQ ID NO: 43 in patented claim 23;
wherein the VH and/or VL of the antibody or antigen binding fragment thereof comprises Framework Regions (FR) derived from a human or a mouse immunoglobulin in patented claim 28;
in a conjugate in patent claim 12;
in a multispecific antibody in claim 14;
in a pharmaceutical composition which comprises a pharmaceutically acceptable carrier and/or an excipient in patented claim 15;
in a pharmaceutical composition according which further comprises a second antibody that specifically binds to PD-1 in patented claim 16;
is in a method for treating a tumor in a subject, wherein the tumor is CLDN18.2 positive, the method comprising administering to the subject in need thereof an effective amount of the pharmaceutical composition of claim 15, which further comprises administering an immunotherapy in patented claim 18-19;
wherein the tumor is a solid tumor of gastric cancer in patented claims 20 and 22,
The claims of ‘265 did not teach: 1) a conjugate wherein the linker drug is
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, but this is obvious in view of ‘804.
804 taught an effective method of treating pancreatic cancer that expressed EGP-1, comprising administering a pharmaceutical composition comprising of the ADC hRS7-CL2A-SN-38 (page 89, [0232] and Fig. 2) and a pharmaceutically acceptable excipient, wherein the antibody was conjugated to the CLA2A-SN-38 linker of
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(page 85 and pages 87-88 [0231]), wherein hRS7-CL2A-SN-38 had a DAR of 5.8 (page 88, Table 7, [0231]).
Regarding instant claims 25-28, 30-37, and 58-73, it would have been obvious for a person having ordinary skill in the art to take ‘265 patented claims 1, 12, 14-16, 18-20, 22-23, and 28 of a method for treating a gastric tumor in a subject, wherein the tumor is CLDN18.2 positive, the method comprising administering to the subject in need thereof an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a multispecific conjugate, wherein the antibody comprises a VH of ‘265 SEQ ID NO:40 and a VL of ‘265 SEQ ID NO:41 and a CH of ‘265 SEQ ID NO: 42 and a CL of ‘265 SEQ ID NO: 43, with human framework sequences, in combination a second antibody that specifically binds to PD-1 as an immunotherapy – and modify the method by: 1) including the CLA2A-SN-38 linker of
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, wherein antibody-CL2A-SN-38 had a DAR of 5.8 and γ is between 5-6 of ’804.
This is obvious because: 1) ‘804 taught an effective method of treating pancreatic cancer that expressed EGP-1, comprising administering a pharmaceutical composition comprising of the ADC hRS7-CL2A-SN-38 and a pharmaceutically acceptable excipient, wherein the antibody was conjugated to the CLA2A-SN-38 linker of
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, wherein hRS7-CL2A-SN-38 had a DAR of 5.8.
There is a reasonable expectation of success because the claims of ‘265 taught the CLDN18.2 antibody was useful in a method of treating cancer and as a conjugate bound to a cytotoxin and: 1) the linker drug
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was effective against cancer cells.
This would produce a method for treating a gastric cancer (instant claims 56-57 and 66), which is a solid tumor (instant claim 65), in a subject, wherein the tumor is CLDN18.2 positive (instant claim 67), the method comprising administering to the subject in need thereof an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier (instant claim 61) and a multispecific (instant claim 37) conjugate, wherein the structure is:
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, wherein the antibody comprises a VH of ‘265 SEQ ID NO:40 and a VL of ‘265 SEQ ID NO:41 and a CH of ‘265 SEQ ID NO: 42 and a CL of ‘265 SEQ ID NO: 43, which is identical to the instantly claimed heavy chain of SEQ ID NO:19 and light chain of SEQ ID NO:20 (instant claim 36) and is further comprised of a heavy chain with instant SEQ ID NO:14 (instant claim 26), and instant SEQ ID NO:1, 21, 3 and an IgG1 CH of instant SEQ ID NO:16 (instant claims 27 and 31-32) and a light chain with instant SEQ ID NO:15, and instant SEQ ID NO:4-6 and kappa light chain CL of instant SEQ ID NO:17 (instant claims 33-34) which have human frameworks (instant claim 30), wherein the DAR is 6.9 and γ is between 6-7 (instant claims 28 and 58-60), in combination a second antibody that specifically binds to PD-1 as an immunotherapy (instant claim 63-64) (instant claims 25, 35, 62, and 68-71).
Claims 25-28, 30-37, 55-62, and 65-67 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12, 15-16, 18, 21-25 of copending Application No. 18/000,174 in view of WO 2014/092804 (Govindan SV et al.).
‘174 taught a bispecific antibody comprising an antibody that binds to CLDN18.2 in copending claims 1-12 15-16, 18, 21-25. ‘174 taught a bispecific antibody comprising an antibody that binds to CLDN18.2, wherein the antibody comprises a VH of SEQ ID NO:6 and a VL of SEQ ID NO:3 copending claim 1, a pharmaceutical composition comprising the bispecific antibody as a conjugate linked to a cytotoxin and a pharmaceutically acceptable carrier in copending claims 18 and 22, a method for treating pancreatic cancer comprising administering to a subject in need thereof the bispecific antibody in copending claim 21.
The claims of ‘174 did not teach: 1) a conjugate wherein the linker drug is
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, but this is obvious in view of ‘804.
‘804 taught an effective method of treating pancreatic cancer that expressed EGP-1, comprising administering a pharmaceutical composition comprising of the ADC hRS7-CL2A-SN-38 (page 89, [0232] and Fig. 2) and a pharmaceutically acceptable excipient, wherein the antibody was conjugated to the CLA2A-SN-38 linker of
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(page 85 and pages 87-88 [0231]), wherein hRS7-CL2A-SN-38 had a DAR of 5.8 (page 88, Table 7, [0231]).
Regarding instant claims 25-28, 30-37, 55-62, and 65-67, it would have been obvious for a person having ordinary skill in the art to take ‘174 patented claims 1, 18, 21-22 of a method for treating a pancreatic cancer in a subject, the method comprising administering to the subject in need thereof an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a bispecific cytotoxin conjugate, wherein the antibody comprises a VH of ‘174 SEQ ID NO:6 and a VL of ‘174 SEQ ID NO:3, with human framework sequences – and modify the method by:
1) including the CLA2A-SN-38 linker of
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, wherein antibody-CL2A-SN-38 had a DAR of 5.8 and γ is between 5-6 of ’804; and 2) treating a cancer positive for CLDN18.2.
This is obvious because: 1) ‘804 taught an effective method of treating pancreatic cancer that expressed EGP-1, comprising administering a pharmaceutical composition comprising of the ADC hRS7-CL2A-SN-38 and a pharmaceutically acceptable excipient, wherein the antibody was conjugated to the CLA2A-SN-38 linker of
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, wherein hRS7-CL2A-SN-38 had a DAR of 5.8.; and 2) CLDN18.2 is the target of the claimed antibody and thus the ADC would target the cancer cells expressing the CLDN18.2 target.
There is a reasonable expectation of success because the claims of ‘174 taught the CLDN18.2 antibody was useful in a method of treating cancer and as a conjugate bound to a cytotoxin and: 1) the linker drug
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was effective against cancer cells; and 2) CLDN18.2 is the target of the claimed antibody and thus the ADC would target the cancer cells expressing the CLDN18.2 target.
This would produce a method for treating a pancreatic cancer (instant claims 56-57 and 66), which is a solid tumor (instant claim 65), in a subject, wherein the tumor is CLDN18.2 positive (instant claim 67), the method comprising administering to the subject in need thereof an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier (instant claim 61) and a bispecific (instant claim 37) conjugate, wherein the structure is:
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, wherein the antibody comprises a VH of ‘174 SEQ ID NO:6 and a VL of ‘174 SEQ ID NO:3, which is identical to a VH of instant SEQ ID NO:14 (instant claim 26), and instant SEQ ID NO:1, 21, 3 and a VL with instant SEQ ID NO:15, and instant SEQ ID NO:4-6 with human framework sequences (instant claim 30), wherein the DAR is 6.9 and γ is between 6-7 (instant claims 28 and 58-60), in combination a second antibody that specifically binds to PD-1 as an immunotherapy (instant claim 63-64) (instant claims 25, 35, 62).
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
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/J.J.S./Examiner, Art Unit 1643
/Karen A. Canella/Primary Examiner, Art Unit 1643