DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The present application is drawn from PCT/US2022/041404, filed 8/24/2022; and claims benefit under 35 U.S.C. 119(e) to U.S. Provisional applications 63/272450, filed 10/27/2021, and 63/236988, filed 8/25/2021.
Status of Claims
Claims 9-53 and 63 are pending and are being examined on the merits.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 26 and 35 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 26 recites the conjugate of claim 25, wherein Z30 is selected from R, K, H, A, G, L, V, I and P. Claim 25 recites the formula III of claim 24, wherein the sequence is L(fGly’)TPSR. Thus, claim 25 defines Z30 as R. Claim 26 fails to further limit the subject matter of claim 25; rather claim 26 broadens the subject matter of claim 25 to alternative residues. That is, claim 26 allows for alternative resides at position Z30, whereas claim 25 explicitly defines the sequence, with no alternatives. This is also true for the X1, X2 and X3 residues of the sequence.
Claims 35 also invokes the same error. Claim 35 depends from claim 34, but broadens the amino acid residues that may be used at positions Z30, X1, X2 and X3 as compared to the explicitly defined sequence of claim 34. Thus, claims 26 and 35 are rejected for failing to further limit the subject matter of the claims upon which they depend.
Examiner suggests amending claim 26 to depend from claim 24, and amending claim 35 to depend from claim 33.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim 31 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 31 recites the conjugate of claims 9, 24 and 27 and provides the required conjugate structure. However, the structure of claim 31 is does not comprise the conjugate of instant claim 9. Specifically, claim 9 requires the conjugates to use that of formula II. The structure of claim 31 comprises the conjugate of formula I, which is not claimed. For example, the structure of claim 31 does not comprise “wherein at least one of Z1, Z2, Z3 and Z4 is C-LB-W12.” Thus, claim 31 is rejected for failing to include all the limitations of the claim upon which it depends.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claims 9-20, 22-30, 32-53 and 63 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 the species of claims 21 and 31, does not reasonably provide enablement for each and every possible variation of formula (II), where R21, R22, R23, Z1, Z2, Z3 Z4, LA, LB and W of formula (II), in addition to all of the variables within the scope of L, form a wide range of ring systems. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
In evaluating the enablement question, several factors are to be considered. In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988); Ex parte Forman, 230 USPQ 546. The factors include: 1) The nature of the invention, 2) the state of the prior art, 3) the predictability or lack thereof in the art, 4) the amount of direction or guidance present, 5) the presence or absence of working examples, 6) the breadth of the claims, and 7) the quantity of experimentation needed.
HOW TO MAKE: The nature of the invention in the instant case, has claims which embrace compounds of the formula (II), where R21, R22, R23, Z1, Z2, Z3 Z4, LA, LB and W of formula (II) form a wide range of ring systems; see instant claims 9, 13 and 17 drawn to the compound of formula II as well as various linkers. The magnitude of possible ring systems are not described in the disclosure in such a way that one of ordinary skill in the art would know how to prepare the various compounds suggested by claim 9. For example, accounting for the numerous options for each R side chain, there are thousands of possible variations encompassed in instant claim 9. Further, each of linkers, LA and LB (claims 13 and 17), encompass thousands of various combinations wherein each T and V are independently selected from the numerous options for each. Thus, when combining the thousands of variants of the compound of formula II across the thousands of variants of each of LA and LB, the total number of embodiments encompassed by the conjugate of the claims extends into the millions. In view of the lack of direction provided in the specification regarding starting materials, the lack of working examples, and the general unpredictability of chemical reactions, it would take an undue amount of experimentation for one skilled in the art to make the claimed compounds, across the enormous scope of the claims, and therefore practice the invention.
The instant specification teaches one example of formula II in total (para. 00431). The example does not possess the variable W of formula II.
HOW TO USE: Claim 47 is drawn to the method of treating cancer. Any evidence presented must be commensurate in scope with the claims and must clearly demonstrate the effectiveness of the claimed compounds. 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. For example, the specifications describe wherein the cancer chemotherapeutic agent is topoisomerase inhibitor (pg. 142, para. 00507). While the treatment of, for example, breast cancer (claim 48) has been linked with topoisomerase I inhibitors, it does not recognize use of such inhibitors as broad based drugs for treating all disorders instantly embraced (i.e. any cancer).
Further, the specifications define “treatment” as including “prevention” of the development of clinical symptoms (specifications, pg. 154, para. 00546). Where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). Thus, the applicants have specifically defined treatment to include preventing disease.
The treatment and/or prevention of any cancer generally cannot possibly be considered enabled.
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 Liebel-Flarsheim Co. v. Medrad, Inc. 481 F.3d 1371, 82 USPQ2d 1113; 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).
By way of background, four cases are of particular relevance to the question of enablement of a method of treating cancers broadly or even generally:
In In re Buting, 57 CCPA 777, 418 F.2d 540, 163 USPQ 689, the claim was drawn to “The method of treating a malignant condition selected from the group consisting of leukemias, sarcomas, adenocarcinomas, lymphosarcomas, melanomas, myelomas, and ascitic tumors” using a small genus of compounds. The Court decided that human testing “limited to one compound and two types of cancer” was not “commensurate with the broad scope of utility asserted and claimed”.
In Ex parte Jovanovics, 211 USPQ 907 the claims were drawn to “the treatment of certain specified cancers in humans” by the use of a genus of exactly two compounds, the N-formyl or N-desmethyl derivative of leurosine. Applicants submitted “affidavits, publications and data” for one of the compounds, and a dependent claim drawn to the use of that species was allowed. For the other, no data was presented, applicants said only that the other derivative would be expected to be less effective; claims to the genus were refused.
In Ex parte Busse, et al., 1 USPQ2d 1908, claims were drawn to “A therapeutic method for reducing metastasis and neoplastic growth in a mammal” using a single species. The decision notes that such utility “is no longer considered to be “incredible”, but that “the utility in question is sufficiently unusual to justify the examiner's requirement for substantiating evidence. Note also that there is also a dependent claim 5 which specified “wherein metastasis and neoplastic growth is adenocarcinoma, squamous cell carcinoma, melanoma, cell small lung or glioma.” The decision notes that “even within the specific group recited in claim 5 some of the individual terms used actually encompass a relatively broad class of specific types of cancer, which specific types are known to respond quite differently to various modes of therapy.”
In Ex parte Stevens, 16 USPQ2d 1379 a claim to “A method for therapeutic or prophylactic treatment of cancer in mammalian hosts” was refused because there was “no actual evidence of the effectiveness of the claimed composition and process in achieving that utility.”
Pursuant to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), one considers the following factors to determine whether undue experimentation is required: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
Breadth of claims and nature of invention:
The claimed subject matter pertains to a method of preventing or treating many different cancers by administering an antibody-drug-conjugate (ADC) of formula II, wherein the antibody is an anti-TACSTD2 (i.e. Trop2) antibody. Applicant’s specification describes many such cancers that may be treated by the instant invention, including carcinomas, sarcomas, leukemias and lymphomas, wherein each category includes a list further defining different specific types of cancer which may be treated (pg. 155, paras. 00551-00556).
State of the art and level of ordinary skill:
At the time of the effective filing date, the level of ordinary skill to treat cancer was high, requiring advanced knowledge of medicine and cell biology, typically requiring a doctoral degree and several years of experience. One of skill in the art is well-aware that cancer is difficult to prevent and treat, and there are numerous molecular mechanisms which may drive cells to become cancerous, from generic abnormalities to environmental factors. The variety of molecular mechanisms for cancer require highly personalized treatment for each type of cancer, depending on the patient. However, the instant disclosure does not provide sufficient in vitro or in vivo evidence showing that the instantly claimed method can counter-act the cause or the manifestation of any cancer as defined above in order to prevent or ameliorate the disease.
To elaborate, Fidler (Human Vaccines & Immunotherapeutics, 2012) teaches that cancer is a highly heterogeneous disease, driven by genomic variability, which presents challenges to therapy. Specifically, a heterogeneous disease cannot be treated by a homogenous therapy. One skilled in the art would appreciate that a single specific therapy would be unlikely to treat all types of cancers equally.
It is important to note that tumors may need to be treated quite differently even though they are tumors of the same organ. For example, the drugs used most often to treat Wilms tumor, the most common malignant tumor of the kidneys in children, are chemotherapy drugs actinomycin D and vincristine (Wolff, 1975). However, such drugs are almost never used with renal cell carcinoma, which is also a kidney cancer, and which is treated, although without much success, with immunotherapy using the cytokines interleukin-2 and interferon-alpha, rather than chemotherapy (Bleumer et al., 2003). However, such immunotherapy has never been established as effective in non-clear cell RCC forms such as papillary renal cell carcinoma. Despite strenuous efforts over a period of decades, no chemotherapeutic agent has ever been found effective against this cancer (Sepe et al., 2021). Cancers of the stomach can be lymphomas, GISTs, carcinoid tumors, carcinomas, or soft tissue sarcomas, and for a single agent to be effective against all or even most of these categories would be contrary to what is known in oncology.
The level of predictability of the art:
Pharmaceutical therapies in the absence of in vivo clinical data are unpredictable for the following reasons: (1) the protein may be inactivated before producing an effect, i.e. such as proteolytic degradation, immunological inactivation or due to an inherently short half-life of the protein; (2) the protein may not reach the target area because, i.e. the protein may not be able to cross the mucosa or the protein may be adsorbed by fluids, cells and tissues where the protein has no effect; and (3) other functional properties, known or unknown, may make the protein unsuitable for in vivo therapeutic use, i.e. such as adverse side effects prohibitive to the use of such treatment. See page 1338, footnote 7 of Ex parte Aggarwal, 23 USPQ2d 1334 (PTO Bd. Pat App. & Inter. 1992).
The amount of direction provided by the inventor, the existence of working examples, and the quantity of experimentation needed to make or use the invention based on the content of the disclosure:
The specifications describe generating a linker-payload of RED-106, containing a 4AP group according to scheme 1 or 2 (pg. 159, example 1; pg. 163, example 2). Further, the RED-106 is conjugated to a TACSTD2 antibody to form the ADC (pg. 166, example 3). The ADC was tested for cytotoxicity against cell lines Bx-PC-3, NCI-H87, NCI-H292 and MDA-MB-468, in vitro (pg. 168, 00603), as well as in vivo against NCI-H292 cells transplanted in mice (pg. 169, para. 00605). The cells lines are all epithelial cancers (pancreatic, gastric, pulmonary and breast, respectively). The specifications also describe synthesis of belotecan construct 21 (pg. 174, para. 00627, example 5), its conjugation to Sacituzumab antibody (example 6, pg. 180, para. 00636), and its effectiveness against the breast cancer cell line MDA-MB-469, in vitro, and the pulmonary carcinoma cell line NCI-H292 transplanted in mice, in vivo (pg. 181, para. 00640, examples 7-8). Thus, the examples disclose making 2 ADCs, and their effectiveness against 4 cancer cell lines. Each ADC was conjugated to an anti-Trop2 antibody.
The specification does not adequately teach how to effectively formulate the conjugate-linker of formula II across array of different R groups, across the array of different linkers, and across the array of different cytotoxic agents. Further the specifications do not teach how to prevent and treat the breadth of cancers or reach an appropriate beneficial therapeutic endpoint by administering the ADC. The specification does not teach how to extrapolate data obtained from various in vitro and in vivo observations as well as clinical experience with the antibody to the development of effective methods of preventing or treating the plethora of the cancers broadly encompassed by the claimed invention. Applicant’s specification offers no data to indicate that administration of the recited ADC would be successful in treating every conceivable cancer. For example, the claims are to an ADC comprising an anti-Trop2 antibody. However, Trop2 is primarily expressed on endothelial cancer subtypes, and is not expressed on all cancer types, such as blood cancers. Therefore the use of an anti-Trop2-based ADC would not be enabled for treating cancers such as leukemia or non-epithelial solid tumors such as melanoma. It is clear that the basis for the effectiveness of the ADC is to bind to Trop2 on cancer cells, such that the cytotoxic drug may kill the cell. However, an artisan looking to treat AML or ALL is not enabled to do so given the ADC of the invention requires a Trop2-expressing cancer.
Given the fact that, historically, the development of new cancers drugs has been difficult and time consuming, the quantity of experimentation needed is expected to be great. For example, constructing an ADC of conjugate-linker with a maytansinoid may require selection of different side chain moieties of formula II, or alternative variants of linkers LA and LB, versus an ADC with a camptothecine. Regarding general synthetic procedures, the specifications describe “during any of the processes for preparation of the subject compounds, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned,” (pg. 159, para. 00567). However, the disclosure does not teach the artisan which instances, across the enormous scope of claimed structures, it will be necessary or desirable to do so, which sensitive or reactive groups are concerned, or what steps are the skilled artisan is to take in order to protect the sensitive groups. Further, as described above, a particular chemotherapeutic agent will have varying effectiveness across phenotypically distinct tumor cells, whereby some tumors are resistant to some chemotherapeutic agents, as described for RCC above. Thus, the specifications should enable the artisan to know which agent should be formulated in the ADC based on the cancer type being targeted for treatment; such that the cancer expresses Trop2, the agent has cytotoxicity to the specific cancer cells, and the synthesis of the conjugate-linker-drug, as well as the modified antibody, are enabled.
MPEP 2164.01(a) states, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).”
In view of the lack of direction provided in the specification regarding starting materials, the relatively few working examples, and the general unpredictability of chemical reaction, it would take an undue amount of experimentation for one skilled in the art to make the claimed compounds and practice the invention for treating any type of cancer. To be enabling, the specification of a patent must teach those skilled in the art how to make and use the scope of the claimed invention without undue experimentation. Here the claims encompass millions of structural variants of the conjugate-linker, further incorporating various conjugated cytotoxic drug moieties, each of which must be considered, structurally, for integration into the conjugate-linker structure. The applicants are not entitled to preempt the efforts of others. The test for determining compliance with 35 U.S.C. § 112, is whether the applicants have clearly defined their invention.
Where the utility is unusual or difficult to treat or speculative, the examiner has authority to require evidence that the tests relied upon are reasonably predictive of in vivo efficacy by those skilled in the art. See In re Ruskin, 148 USPQ 221; Ex parte Jovanovics, 211 USPQ 907; MPEP 2164.05(a).
Patent Protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable. Tossing out the mere germ of an idea does not constitute enabling disclosure. Genentech Inc. v. Novo Nordisk 42 USPQ2d 1001.
As stated in the MPEP, 2164.08 ''[t]he 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. ln re Wright, 999 F.2d 1557, 1561 27 USPQ2d 1510, 1513 (Fed. Cir. 1993). Nevertheless, not everything necessary to practice the invention need be disclosed. In fact, what is well known is best omitted. In re Buchner, 929 F.2d 660, 661, 18 USPQ2d 1331, 1332 (Fed. Cir. 1991). AII that is necessary is that one skilled in the art be able to practice the claimed invention, given the level of knowledge and skill in the art. Further the scope of enablement must only bear a reasonable correlation to the scope of the claims. See, e.g., In re Fisher, 427 F.2d 833, 839,166 USPQ 18, 24 (CCPA 1970). As concerns the breadth of a claim relevant to enablement, the only relevant concern should be whether the scope of enablement provided to one skilled in the art by the disclosure is commensurate with the scope of protection sought by the claims. In re Moore, 439 F.2d 1232, 1236, 169 USPQ 236, 239 (CCPA 1971). See also Plant Genetic Sys., N.V. v. DeKalb Genetics Corp., 315 F.3d 1335, 1339, 65 USPQ2d 1452, 1455 (Fed. Cir. 2003) (alleged pioneer status of invention irrelevant to enablement determination.''
Regarding cancer “prevention” as encompassed by treatment; due to the high level of unpredictability in the area of disease prevention, particularly cancer prevention (Meyskens et al., 2016), the skilled artisan would need significant guidance in preventing cancer by practicing the claimed method. The skilled artisan recognizes that keeping individuals free of cancer indefinitely is an intractable proposition, if not now wholly impossible, given, for example, that cancers are widely heterogeneous diseases, having widely varying pathologies and etiologies, and with causes that are multifactorial and as yet only partially characterized and poorly understood. It is generally recognized that a disease cannot be prevented unless and until its causes are fully appreciated and understood to a degree that it becomes possible to intercede effectively to block its onset or development by any cause. The only way a cancer can be prevented, before it has even begun to manifest, if through avoidance of exposure to carcinogens, vaccination or genetic engineering (Meyskens et al., 2016). Here, the invention is to an ADC comprising a cytotoxic agent, which cannot prevent a cell from becoming cancerous, it can only kill the cell after the pathology has set in.
In conclusion upon careful consideration of the Wands factors that are used to determine whether undue experimentation is required to practice an invention, the amount of direction provided by the inventor and the working examples provided, as filed, is not deemed sufficient to enable the skilled artisan to make and/or use the invention commensurate in scope with the instant claims at the time the application was filed without undue experimentation. Specifically, the vast range of variant ring systems of claim 9 impart undue experimentation upon the skilled artisan to make and use the invention; thus claim 9 is rejected. As claims 10-20, 22-30, 32-53 and 63 depend from claim 9, yet fail to rectify the enablement issues, claims 10-20, 22-30, 32-53 and 63 are also rejected. Further, the methods of claim 47 are not enabled as 1) undue experimentation is required of the skilled artisan to treat any and all types of cancer, and 2) undue experimentation is required of the skilled artisan to use the product of claim 9 to “prevent” any type of cancer. As applicants have re-defined the term “treatment” in the specifications, so as to include “preventing”, it is suggested that applicants use a term synonymous with ameliorating or reducing, in place of “treating”. Further, as the conjugates require a TACSTD2 antibody for targeting the chemotherapeutic drugs to the tumor, the type of cancer must necessarily express TACSTD2 (i.e. Trop2) in order to be considered enabled for amelioration with the product of claim 9.
Claim Rejections - 35 USC § 112(a)
Claims 42 and 44 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 following quotation from section 2163 of the Manual of Patent Examination Procedure is a brief discussion of what is required in a specification to satisfy the 35 U.S.C. 112 written description requirements for a generic claim covering several distinct inventions:
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice... reduction to drawings...or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus... See BU Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
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.
Thus, when a claim covers a genus of inventions, the specification must provide written description support for the entire scope of the genus. Support for a genus is generally found where the applicant has provided a number of examples sufficient so that one in the art would recognize from the specification the scope of what is being claimed.
Claim 42 is rejected as lacking adequate descriptive support for possession of a genus of antibodies or antigen-binding fragments that “competes for binding to TACSTD2” with the anti-TACSTD2 antibody comprising the CDRs as described in claim 42. In support of the claimed genus, the specifications disclose only the antibody of instant claim 43 or that of instant claim 44. Instant claim 44, further recites an antibody having “70% or greater” sequence identity to the VH of SEQ ID NO: 2 and “70% or greater” sequence identity to the VL of SEQ ID NO: 7. Specifically the amino acid sequences of the 6 CDRs, comprising the antigen binding domain, and the necessary structural features that impart functionality in terms of specificity and affinity, of each of the antibodies is not disclosed. Thus, instant claim 42 encompasses a genus of anti-TACSTD2 antibodies that comprise unidentified CDRs, variable heavy and light chains, or full heavy and light chain sequences; thereby providing no structural properties of the claimed antibodies. Further, instant claim 44 encompasses a genus of anti-TACSTD2 antibodies, whereby the VH and VL are at least 70% identical to instant SEQ ID NOs: 2 and 7, respectively. Instant SEQ ID NO: 2 is 121 amino acids in length; thus allowing for up to 36 amino acid substitutions. Instant SEQ ID NO: 7 is 107 amino acids in length, thus allowing for up to 32 amino acid substitution. No guidance is provided as to which residues may be substituted, and with which amino acids. There are 20 alternate amino acids that may be substituted at up to at least 30 residues, in any combination, at any location, in the VH or VL. Thus, the claims encompass a vast number of variant sequences. For example, substituting any one of 20 amino acids, across 10 consecutive residues, in any order, allows for 184,756 different combinations. In the instant claims, there are > 30 residues that may be substituted, and which do not need to be consecutive; thus there are millions of combinations of amino acid substitutions encompassed by the claims. Further, the claims do not exclude substitutions in the CDRs, whereby 30 substitutions may occur within the CDRs or whereby the substitutions may encompass mutating an entire CDR. Thus the broadest reasonable interpretation of the antibodies of claim 44 is to a genus of variant anti-TACSTD2 antibodies comprising unidentified VH and VL CDRs.
In support of the claimed genus(es) of anti-TACSTD2 antibodies, the specification disclose 2 antibodies, the antibody of Table 4 (pg. 121), and the antibody comprising the CDRs 1-6 of instant claim 43, whereby the CDRs are identical to those of the antibody of Table 4, with the exception of a single amino acid residue substitution in the HCDR1 domain (NYGMN is NYNMN). However, no guidance is provided as to which residues may be substituted, or with alternative amino acids; only the specific embodiments of 2 antibodies are disclosed, thus only a G-to-N substitution in HCDR1 is taught. When determining the representative examples and the art, it is important to consider whether there is evidence of a singular shared structural feature which imparts the defining property of the claimed genus, and which would necessarily be present in every species of the claimed genus. In this case, only 2 antibodies are disclosed which bind TACSTD2, and no variants which are 70% or greater in sequence identity to any of the claimed variable domains are disclosed. Further, there is no teaching of where the substitutions may be made in variant embodiments, or what the defining structural feature of all claimed species are required to have, in order to impart the required properties of functionally binding TACSTD2.
Regarding the state of the art; it is known in the art that the antigen binding domain of an antibody requires the 6 complementarity determining regions (CDR) of the heavy and light chains, whereby the 3 CDRs of the heavy chain and the 3 CDRs of the light chain are structurally inter-dependent in forming the unique binding pocket of the antibody paratope region; and thus the CDRs constitute critical aspects of the antibody paratope and ultimately impart the paratope-epitope binding functionality with regard to specificity and affinity (for review see MacCallum et al., 1996). However, the structure-to-function correlation continues to be highly unpredictable. For example, Chen et al., (1992) teaches that a single amino acid substitution in the VH CDR2 of PC-specific T15 antibody could increase, decrease or ablate binding the target antigen (abstract, Fig. 3), and this occurred in an unpredictable manner based on which residue was mutated. Similarly, a single point mutation in the heavy chain CDR3 region of the high affinity anti-VEGF antibody G6.31, could in some cases enhance, or otherwise completely ablate binding to the target antigen, and this also occurred in an unpredictable manner (Koenig et al., PNAS, 2017). That is, only screening each mutation individually provided insight as to the resulting changes in functionality. In some cases this extends even beyond the CDRs. Within the framework regions, Koenig et al. (PNAS, 2017) teaches that various amino acid point mutations can increase or decrease binding or neutralization capacity. Some amino acid residues are more tolerant to substitution, while other “conserved” residues are less tolerant, such that a single amino acid substitution may defunctionalize the antibody (pg. E487, Fig. 1). Thus, while antibodies share certain characteristics such as Fc regions or hinge regions, these regions are not correlated with the binding function of the antibody. Conversely, the hyper-variable regions, comprising the complementary set of 6 CDRs, are well established in the art as the portion of the binding regions which impart the specificity of the antibody; and yet, there is no way to look at an amino acid sequence and envision, a priori, whether the combination of six CDRs will bind a particular epitope, even when the CDRs are highly related, without teachings of the basic shared amino acid residues that are sufficient to impart functional binding across all variants. Further, even when provided with several related antibodies that bind the desired target, this does not represent the astronomical and potentially unknowable breadth of all possible amino acid sequences which will result in the desired binding properties. This is exemplified by the Court decision in Abbvie (Abbvie v Janssen 759 F.3d 1285 (Fed. Cir. 2014)), where Abbvie developed over 200 antibodies that shared 99.5% identity in the variable regions (pg. 7) and which bound the target, but in no way allowed one to envisage the unique structure of Centocor’s antibodies which bound the same target but shared only 50% sequence similarity (see table on pg. 11). Thus, when claiming a genus of antibodies based on their binding to a common target, the representative examples must cover the full scope of structural variabilities which encompass all species variants that would bind the target.
Moreover, the decision arrived at in Amgen v. Sanofi, 872, F.3d 1367 (Fed. Cir. 2017) supports expanded analysis of whether a claim drawn to an antibody being specific for an epitope, even a specific epitope, permits an applicant to pursue all possible antibodies that are capable of being produced against such an epitope. Specifically, “disclosure of an antigen fully characterized by its structure, formula or physical properties does not, without more, provide adequate written description of an antibody claimed by its binding affinity to that antigen,” (Amgen v Sanofi, 872, F.3d 1367 (Fed. Cir. 2017)). Presently, the claimed genus of antibodies of instant claim 42 are only defined only by functional properties, no specific structure is recited.
Section 2163(II)(A)(3)(a)(ii) of the MPEP states that the written description for a claimed genus may be satisfied through either a) a representative number of species, or b) disclosed correlation between function and structure. Regarding claim 44, the applicants do not provide any variants of the claimed embodiments, in which alternative mutations were made, which were reduced to practice; nor do they identify the shared structural properties of the variants, such as the CDR residues, that would define the genus beyond the desired functionality. Currently the essential property of binding TACSTD2 is imparted by the specific CDRs of the two species of anti-TACSTD2 antibodies that have been reduced to practice; and that accounts for only 2 examples out of millions of potential embodiments, as claimed. Specifically, the physical features (or amino acid residues encoding said features) which impart the property of binding the same epitope of TACSTD2 should be disclosed. Further, a description of the type and number of amino acid residue substitutions that may be made at such identified positions within the sequence, that result in “at least 70%” sequence identity to a selected sequence, would be essential in determining the degree of variability that may be allotted in total sequence identity. This lack of definition complicates the determination of the boundaries of the claimed genus with regard to which, as of yet unidentified, species variants (variable domains with > 70%) would be anticipated, a priori, by one skilled in the art, to fall within the scope of the claims. Without the identification of the necessary shared structural properties of all species variants that fall within the scope of the genus, it may be that an antibody species with < 70% sequence identity to either the VH or VL of SEQ ID NOs: 2 and 7, respectively, would still bind to TACSTD2; or conversely, that antibodies with > 99% sequence identity, but comprising a deleterious mutation in a CDR region would lose functional binding to TACSTD2.
In view of this uncertainty, the lack of a representative number of examples of the claimed genus, and the lack of identification of any shared structural feature, which is necessarily present in every variant species and which imparts the desired functionality, claims 42 and 44 are rejected for lack of adequate written description support.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 9-30, 32-41, 44-53 and 63 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 11,564,989; issued 1/31/2023 in view of Govindan et al., (US Patent 7,238,785; issued 7/3/2007) and Barfield et al., (US Patent 9,540,438; issued 1/10/2017).
Patent ‘989 claims camptothecine antibody-drug conjugates and methods of use. Specifically, patent ‘989 claims a conjugate of formula I (claim 1), which is identical to the conjugate core of instant claim 9. Patent ‘989 claims wherein W is a polypeptide. Further, patent ‘989 claims a compound of formula II attached to the conjugate of claim 1 (claim 2), and comprising a linker (claims 3-8), or a second linker (claims 9-14), or whereby the conjugate is one of the selected molecules (claim 15).
The core of the conjugate of ‘989 claim 1 (formula I) is identical in structure to that of instant claim 1 (formula II). The full conjugate construct, comprising the core, two linkers (LA and LB), and two compounds, which are both camptothecine (e.g. SN-38), of US ‘989 claim 15, embodiment #22 (col. 371, bottom), is 100% identical to the construct of instant claim 21.
Thus, US ‘989 claims the same conjugate-linker-drug compounds, whereby the compound is linked to a polypeptide (W) as that of the instant claims. However, US ‘989 does not claim wherein the polypeptide is a modified TACSTD2 antibody for HIPS conjugation to the conjugate/drug compound.
Govindan et al. teaches anti-TACSTD2 antibodies. Govindan teaches EGP-1 is alternatively referred to as TROP2 (col. 3, lines 62-63), which is another name for TACSTD2 (see instant specs., pg. 2, para. 0005). Govindan claims humanized RS7 antibody, as an anti-EGP-1 antibody, wherein the antibody comprises the LCDRs of SEQ ID NOs: 28-30 and the HCDRs of SEQ ID NOs: 31-33 (col. 79, claim 1). Govindan teaches the hRS7 antibody comprises the VH of SEQ ID NO: 10 and the VL of SEQ ID NO: 7 (col. 6, lines 28-30; Fig. 3).
The VH of Govindan SEQ ID NO: 10 is 100% identical to the VH instant SEQ ID NO: 2, and the VL of Govindan SEQ ID NO: 7 is 100% identical to the VL of instant SEQ ID NO: 7. Thus, Govindan teaches the anti-TACSTD2 of instant claim 44, with 100% identity.
Govindan also teaches the antibody, or a fragment thereof, may be used in a drug conjugate. Specifically, Govindan teaches another object of the present invention is to provide a cancer cell targeting therapeutic conjugate that comprises the anti-EGP-1 Mab or fragment thereof, which is bound to a suitable therapeutic agent; suitable therapeutic agents include antimitotic agents (e.g. maytansine) or camptothecins (e.g. SN-38; col. 4, lines 38-56). Further, Govindan teaches the antibody comprises the constant and hinge regions of IgG1 (col. 9, lines 37-39). Thus, Govindan teaches anti-TACSTD2 antibodies and their use in ADCs with cancer therapeutic drugs as a cancer cell targeting therapeutic conjugate.
However, Govindan does not teach whereby the anti-TACSTD2 antibodies comprise an aldehyde-tagged residue for conjugation.
Barfield et al. teaches aldehyde-tagged immunoglobulin polypeptides and methods of use (title). Barfield teaches the present disclosure provides aldehyde-tagged immunoglobulin polypeptides that can be converted by a formylglycine-generating enzyme (FGE) to produce a 2-formylglycine(Fgly)-modified Ig polypeptide; and that a FGly-modified Ig polypeptide can be covalently and site-specifically bound to a moiety of interest to provide an Ig conjugate (abstract). Barfield teaches exemplary reactive partners include a cysteine or serine of a sulfatase motif and an FGE, which react to form a reaction product of a converted aldehyde containing an FGly in lieu of cysteine or serine; other exemplary reactive partners include an aldehyde of a formylglycine (FGly) residue of a converted aldehyde tag and an “aldehyde-reactive reactive partner,” (col. 9, lines 21-30). As FGEs are endogenous to many cell types, Barfield teaches a “sulfatase motif” may also be referred to as an FGE-modification site (col. 11, lines 52-54). Barfield teaches a converted aldehyde tagged Ig polypeptide is reacted with a reactive partner containing a moiety of interest to provide for conjugation of the moiety of interest to the FGly residue of the converted aldehyde tagged Ig polypeptide (col. 15, lines 16-25). Modified Ig polypeptides having a modified aldehyde tag are generally described by comprising a modified sulfatase motif of the formula: X1(FGly’)X2Z2X3Z3, wherein Z2 is either a proline or alanine residue, Z3 is a basic amino acid, X2 and X3 can be any amino acid, though usually an aliphatic amino acid, and X1 may be present or absent (col. 15, lines 25-50). Barfield provides specific examples of sulfatase motifs, whereby the cysteine residue would be converted to an FGly residue, such as the LCTPSR motif of SEQ ID NO: 17 (col. 15, line 1), which may be considered L(FGly)TPSR after conversion by the FGE enzyme. Thus, Barfield teaches aldehyde-tagged Ig polypeptides comprising an FGly residue.
Regarding the location of the sulfatase motif comprising the FGly residue within an antibody, Barfield teaches the Ig polypeptide includes an Ig constant region, such as the heavy chain CH1, CH2 or CH3 domains, or an Ig light chain constant region (col. 17, lines 8-20). Barfield teaches, for example, Figure 1 depicts the possible modification sites for generation of an aldehyde tagged polypeptide, whereby the regions are shaded (col. 1, lines 43-60). For example, one such site is the SLSPGK at the C-terminus of the heavy chain conserved region of Fig. 1A (HC residues 446-450). Barfield modifies the heavy chain to comprise the LCTPSR sulfatase motif, whereby the cysteine will be converted to FGly by FGE. For example, Barfield depicts a CD22 IgG1 heavy chain, whereby the heavy chain constant region sequence SLSPGK is modified to include the LCTPSR sulfatase motif; thus resulting in a SPGSL(fGly’)TPSRGS sequence (Fig. 17B, underlined; re. instant claims 28-29). Similarly, Barfield teaches inserting a sulfatase motif in Ig light chain constant regions, whereby the motif is inserted at the identified modification site comprising the sequence DNALQSGN (Fig. 1A, LC, residues 173-180). Figure 20B depicts the resulting modified kappa light chain comprising the LCTPSR motif positioned in the DNALQSGN modification site, resulting in a sequence of KVDNALCTPSRQSGNSQ (Fig. 20B, underlined; re. instant claims 33-34). Similarly, Barfield teaches inserting a sulfatase motif in an Ig heavy chain CH1 region (i.e., re. instant claims 37-38). Barfield teaches a HC CH1 modification site of sequence NSGALTSG (Fig. 1A, HC, residues 163-170). Barfield teaches inserting the LCTPSR motif in the modification site, whereby the resulting sequence is SWNSGALCTPSRGVHTFP (Fig. 9B, underlined). Thus, Barfield teaches different sulfatase motifs, or the corresponding FGly aldehyde amino acid sequences, that may be inserted at different modification sites of Ig constant domains, including at the C-terminus of the heavy chain, the CH1 domain of the heavy chain or the C-terminus of a kappa light chain.
It would have been obvious to one of skill in the art to attach the conjugate core/linker/drug molecule of US patent ‘989 to the anti-TACSTD2 antibodies of Govindan, whereby the attachment site of the conjugate/drug occurs via a site specific covalent bond to an aldehyde-tagged motif of the Ig heavy or light chain constant region of the antibody, as taught by Barfield. One would have been motivated to do so in order to generate a cancer cell targeting therapeutic targeting an antimitotic agent (e.g. maytansine) or camptothecin to TACSTD2-expressing cancer cells, as taught by Govindan. There would have been a reasonable expectation for success given that 1) the conjugate/linker/drug molecule may be attached to an antibody polypeptide, as taught by patent ‘989, 2) the anti-TACSTD2 antibody comprises an IgG heavy chain and light chain constant region, as taught by Govindan, and 3) that IgG constant regions may be modified to comprise a sulfatase motif which will be converted to an aldehyde such that site specific covalent bond will form between the antibody constant region and the conjugate/linker/drug molecule, as taught by Barfield. Thus, the invention as a whole was obvious to one of skill in the art at the time the invention was made.
Regarding claims 9-21; the combination molecule of US ‘989, Govindan and Barfield makes obvious the conjugate of instant claims 9-12, comprising the linkers of instant claims 13-20. Specifically, US ‘989 teaches the conjugate structure of instant claim 21, with 100% identity.
Regarding claims 22-30, 32-41 and 44; the combination ADC of US ‘989, Govindan and Barfield, makes obvious wherein the antibody is an IgG1 antibody and/or an IgG1 kappa antibody of instant claims 22-23, and whereby the antibody comprises a sequence of formula III (i.e. L(fGly’)TPSR), in the modification sites, as described above, of instant claims 24-30 and 32-41. Further, Govindan teaches the antibody of claim 44, thus making obvious claim 44.
Regarding claims 45-53 and 63; US ‘989 claims a pharmaceutical composition and a method of administering the construct (claims 16-17), thus the combination of US ‘989, Govindan and Barfield, makes obvious instant claims 45-46 and 63. Further, Govindan teaches EFP-1 (i.e. Trop2 or TACSTD2) is expressed primarily by carcinomas such as carcinomas of the breast (col. 8, lines 3-5). And teaches administering compounds for the treatment of (the triple negative breast cancer cell line) MDA-MD-468 human breast carcinoma xenografts in nude mice (col. 41, lines 61-62). Thus the combination of US ‘989, Govindan and Barfield make obvious the methods of instant claims 47-50. Govindan also teaches the treatment of a breast cancer patient having relapsed adenocarcinoma of the breast, with cervical lymph node and left lung metastases. Thus, the combination methods of US ‘989, Govindan and Barfield make obvious wherein the breast cancer is metastatic and/or relapsed, of instant claims 51-53.
Claims 9-30, 32-41, 44-53 and 63 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15, 34 and 36 of copending Application No. 18/958957 in view of Govidan et al., (US Patent 7,238,785; issued 7/3/2007) and Barfield et al., (US Patent 9,540,438; issued 1/10/2017).
Application ‘957 claims a method of treating cancer in a subject comprising administering the conjugated of formula I (claim 1), which is identical to the conjugate core of instant claim 9. App. ‘957 claims wherein W is a polypeptide. Further, app ‘957 claims a compound of formula II attached to the conjugate of claim 1 (claims 1-2), and comprising a linker (claims 3-8), or a second linker (claims 9-14), or whereby the conjugate is one of the selected molecules (claim 15).
The core of the conjugate of ‘957 claim 1 (formula I) is identical in structure to that of instant claim 1 (formula II). The full conjugate construct, comprising the core, two linkers (LA and LB), and two compounds, which are both camptothecine (e.g. SN-38), of app ‘957 claim 15, embodiment #23 (claims, pg. 28, top), is 100% identical to the construct of instant claim 21.
Thus, application ‘957 claims the same conjugate-linker-drug compounds, whereby the compound is linked to a polypeptide (W) as that of the instant claims.
However, app ‘957 does not claim wherein the polypeptide is a modified TACSTD2 antibody for HIPS conjugation to the conjugate/drug compound.
Govindan et al. teaches the RS7 anti-TACSTD2 antibodies of instant claim 44, comprising the VH instant SEQ ID NO: 2 and the VL of instant SEQ ID NO: 7, with 100% identity, as described above. Govindan teaches the antibody is an IgG1, as well as teaching the antibody as a ADC, with therapeutic agents including antimitotic agents (e.g. maytansine) or camptothecins, as described above. Further, Govindan teaches methods of treating TACSTD2-expressing cancers comprising administering the ADC, including wherein the cancer is triple negative breast cancer, which may be relapsed and/or metastatic, as described above.
However, Govindan does not teach whereby the anti-TACSTD2 antibodies comprise an aldehyde-tagged residue for conjugation.
Barfield et al. teaches aldehyde-tagged immunoglobulin polypeptides of formula III (instant claim 24), as described above. Barfield also teaches wherein sulfatase motif comprising the FGly may be inserted in an IgG1 heavy chain constant region, or C-terminal, or a kappa light chain constant region, or C-terminal; as well as the resulting amino acid sequence dependent on which location the aldehyde tag is located within the IgG constant region. All as described above and incorporated here.
Thus, app ‘957 teaches the conjugate core-linker-compound molecule attached to a polypeptide, Govindan teaches anti-TACSTD2 antibodies and methods of treating breast cancer, and Barfield teaches modifying IgG1 heavy and light chain constant regions for generating an aldehyde tag, which allows conjugation of drug conjugates with a covalent bond to the aldehyde tag, thus creating an ADC.
It would have been obvious to one of skill in the art to attach the conjugate core/linker/drug molecule of application ‘957 to the anti-TACSTD2 antibodies of Govindan, whereby the attachment site of the conjugate/drug occurs via a site specific covalent bond to an aldehyde-tagged motif of the Ig heavy or light chain constant region of the antibody, as taught by Barfield. One would have been motivated to do so in order to generate a cancer cell targeting therapeutic targeting an antimitotic agent (e.g. maytansine) or camptothecin to TACSTD2-expressing cancer cells, as taught by Govindan. There would have been a reasonable expectation for success given that 1) the conjugate/linker/drug molecule may be attached to an antibody polypeptide, as claimed in app ‘957, 2) the anti-TACSTD2 antibody comprises an IgG heavy chain and light chain constant region, as taught by Govindan, and 3) that IgG constant regions may be modified to comprise a sulfatase motif which will be converted to an aldehyde such that site specific covalent bond will form between the antibody constant region and the conjugate/linker/drug molecule, as taught by Barfield. Thus, the invention as a whole was obvious to one of skill in the art at the time the invention was made.
Regarding claims 9-21; the combination molecule of app ‘957, Govindan and Barfield makes obvious the conjugate of instant claims 9-12, comprising the linkers of instant claims 13-20. Specifically, app ‘957 teaches the conjugate structure of instant claim 21, with 100% identity.
Regarding claims 22-30, 32-41 and 44; the combination ADC of app ‘957, Govindan and Barfield, makes obvious wherein the antibody is an IgG1 antibody and/or an IgG1 kappa antibody of instant claims 22-23, and whereby the antibody comprises a sequence of formula III (i.e. L(fGly’)TPSR), in the modification sites, as described above, of instant claims 24-30 and 32-41. Further, Govindan teaches the antibody of claim 44, thus making obvious claim 44.
Regarding claims 45-53 and 63; app ‘957 claims a method of treating cancer, wherein the cancer is breast cancer (claims 1, 34 and 36), and Govindan teaches pharmaceutical compositions and a methods of administering the construct for the treatment of breast cancer, thus the combination of app ‘957, Govindan and Barfield, makes obvious instant claims 45-46 and 63. Further, Govindan teaches the cancer is a TACSTD2-expressing cancer, which may be triple negative breast cancer, and may be relapsed or metastatic, as described above. Thus the combination of app ‘957, Govindan and Barfield make obvious the methods of instant claims 47-53. This is a provisional nonstatutory double patenting rejection.
Citation of Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. The conjugate of instant claim 31 is rejected for not comprising the conjugate core of formula II, of instant claim 9 and its dependents. Instead, the product of claim 31 relies on the core of non-claimed formula I. However, it is noted that Rabuka et al., (US Patent 9,493,413; issued 11/15/2016) claims conjugates comprising the core of instant formula I, including the molecule of instant claim 31 (Fig. 60; col. 127, bottom).
Conclusion
No claims are allowed.
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/JAMES RYLAND MELCHIOR/Examiner, Art Unit 1644
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
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