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 .
This is the first action on the merits.
Election/Restrictions
Applicant's election with traverse of Group (I) in the reply filed on June 5, 2026 is acknowledged. Group (I), drawn to compounds of formula (I), embraced by claims 1-17 and 35-37 was elected by Applicant. The traversal is on the ground(s) that no search or examination burden is present. This is not found persuasive because MPEP §803 does not apply to 371 national phase applications. As noted in the lack of unity, a special technical feature does not link Groups (I) and (II). Applicant has not pointed to any errors in the Examiner’s analysis of the different inventions. The requirement is still deemed proper and is therefore made FINAL.
Applicant elected, without traverse, the following species:
PNG
media_image1.png
264
627
media_image1.png
Greyscale
,
PNG
media_image2.png
299
297
media_image2.png
Greyscale
, and indicated claims 1, 2 ,4-16 and 35-37 read on said species.
Claims 1-18 and 35-37 are pending and claims 1-17 and 35-37 are under examination. Claim 18 is withdrawn based on the lack of unity.
Priority
Applicant's claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) (PROVISIONAL) or 119(a) (FOREIGN) or under 35 U.S.C. 120 (CONT/CIP), 121(DIV), or 365(c) (WO) is acknowledged. Applicant still has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows: The later-filed application must be an application for a patent application (the parent for an invention which is also disclosed in the prior application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of the first paragraph of 35 U.S.C. 112. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994). The disclosure of the prior-filed applications, Application No. 63156156, 63186581, 63214540 and 63237450, fail to provide adequate support or enablement in the manner provided by the first paragraph of 35 U.S.C. 112 for claims 10, 15 and 17 of this application. The combinations claimed in claims 10 and 15 are not found in any of these provisional documents. Moreover, the first species in claim 17 is not found in any of these provisional documents. There may be other omissions as well. Thus, the effective filing date of the present claims 1-9, 11-14 and 35-37 is the date of the provisional document 63156156, March 3, 2021. However, the effective filing date of the present claims 10, 15 and 17 is the international filing date of March 2, 2022.
Claim Rejections - 35 USC § 112
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 5-8, 10, 11, 13, 15 and 36 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 pre-AIA the applicant regards as the invention.
Regarding claim 5, the term “comprising” is indefinite. The claims are drawn to compounds, and therefore, should be closed.
In claim 6, the R12 on the subformula defined as (4AP) on page 4, lacks antecedent basis.
In claim 6, the phrase, “any two adjacent R12 groups” is vague. Said groups are not adjacent.
Regarding claims 7 and 12, the optional substituents on the T variables is lacks antecedent basis.
Regarding claims 8 and 13, the glycoside lacks antecedent basis.
With regards to claims 10 and 15, the term “absent” is used throughout the claims to define variables. However, if these variables were absent, the linker would not continue beyond said variables. Thus, the claims are indefinite.
With regards to claims 5, 10, 11 and 15, the terms “analog,” “moiety,” and “residue” are used to define ethylene diamines and amino acids and are indefinite. Said terms are a substance or compound obtained from, or regarded as derived from, another substance or compound. However, the specification fails to define said terms. Therefore, the metes and bounds are not known for analog, moiety, or residue.
In claim 36, the claim is drawn to a method but it is not known what the method entails, and thus, the claim is indefinite. The metes and bounds of the claim is not known since the claim does not define the actual method. Moreover, the phrase, “an effective amount” should be added after the term “administering” and the phrase “in need thereof” should be added after the term “subject.”
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-17 and 35-37 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 16 and 17, does not reasonably provide enablement for each and every possible variation of formula (I), where R1, R2, R3, Z1, Z2, Z3 Z4, LA, LB, W1 and W3 of formula (I), 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 R1, R2, R3, Z1, Z2, Z3 Z4, LA, LB, W1, W2 and W3 of formula (I) form a wide range of ring systems and 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 1. For example, accounting for the numerous options for each varaible, there are millions of possible variations encompassed in instant claim 1. Further, each of linkers, LA and LB (claims 5 and 6), 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 (I) 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 about 25 examples of formula (I) spanning pages 226-301. The examples do not possess the variable W3 of formula (I).
HOW TO USE: Claim 37 is drawn to the method of treating cancer and claim 36 is drawn to a general method. 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.
Further, the specifications define “treatment” as including “prevention” of the development of clinical symptoms (specifications, pg. 219, para. 00522). 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 (I). Applicant’s specification describes many such cancers that may be treated by the instant invention, including carcinomas, breast, ovarian, colon, lung, stomach, pancreatic, etc. (pg. 220, para. 00528).
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 branched HIPS linkers that carry two (or more) molecules of the same or different payload per one HIPS moiety and are therefore capable of conjugating two (or more) small molecule payloads per one aldehyde group in a protein in a single conjugation step (FIG. 2). Consequently, the usage of such branched linkers allows the generation of higher DAR site-specific conjugates (e.g., DAR up to 8) with controlled payload placement, which in the context of therapeutic ADCs would result in larger quantities of pharmaceutical agent delivered to the targeted tissue, see pages 1-2 (bridging) of the specification, see pages 1-2 (bridged).
The ADCs were tested for cytotoxicity against cell lines Bx-PC-3, NCI-H87, NCI-H292 and MDA-MB-468, in vitro, as well as in vivo against NCI-H292 cells transplanted in mice, see pages 304-307. The cells lines are all epithelial cancers (pancreatic, gastric, pulmonary and breast, respectively). The specifications also describe synthesis of ADC of compounds 18, 32 and 36, example 5 on page 304, 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, Examples 7-8). Thus, the examples disclose making about 25 ADCs, testing 3 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 (I) 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 a polypeptide, e.g. an 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 a specific antibody will determine which cancer may be treated. For example, if an anti-Trop2-based ADC were used, see page 306, Example 8, said 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.
Moreover, for the ADC to function properly, not just any antibody may be used. The antibody must be modified with 2-formyl glycine, see page 196.
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 (I), 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. 221, para. 00533). 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. 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 what is needed for the antibody to be bind, 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 claims 1-17 are rejected. Further, the methods of claim 35-37 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 modified polypeptide or antibody for targeting the chemotherapeutic drugs to the tumor, the type of cancer must necessarily express a specific antigen, e.g., TACSTD2 (i.e. Trop2) in order to be considered enabled for amelioration with the product of claim 1.
Claims 1-17 and 35-37 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
This is a written description rejection.
The analysis for adequate written description considers the following:
(a) Actual reduction to practice;
(b) Disclosure of drawings or structural chemical formulas;
(c) Sufficient relevant identifying characteristics, such as (i) complete/partial structure, (ii) physical and/or chemical properties, and (iii) functional characteristics when coupled with known or disclosed correlation with structure; and
(d) Representative number of samples.
A lack of adequate written description issue arises if the knowledge and level of skill in the art would not permit one skilled in the art to immediately envisage the product claimed from the disclosed process. See, e.g., Fujikawa v. Wattanasin, 93 F.3d 1559, 1571,39 USPQ2d 1895, 1905 (Fed. Cir. 1996) (a "laundry list" disclosure of every possible moiety does not constitute a written description of every species in a genus because it would not "reasonably lead" those skilled in the art to any particular species); In re Ruschig, 379 F.2d 990, 995, 154 USPQ 118, 123 (CCPA 1967).
An applicant may also show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics.
In particular, the specification as original filed fails to provide sufficient written basis for the scope of the compounds of formula (I), wherein possession is lacking for a genus of 1) polypeptides, e.g., antibodies or antigen-binding fragments; 2) first and second drug; and 3) linkers that tether the drugs to the indole core and the polypeptide. The mere fact that Applicant may have discovered several specific compounds of formulas (I), is not sufficient to claim the entire genus. Moreover, claim 36 is drawn to a general method and claim 37 is drawn to treating and/or preventing cancer generally.
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 Eli 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. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]."
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.
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 1-17 and 35-37 are rejected for lack of adequate written description support.
The rejection is made under 35 USC 112 (a), as written description is lacking.
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 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.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
All the applied references in the following rejections have a common assignee with the instant application. Based upon the earlier effective U.S. filing date of the reference, it constitutes prior art under pre-AIA 35 U.S.C. 102(e). This rejection under pre-AIA 35 U.S.C. 103(a) might be overcome by: (1) a showing under 37 CFR 1.132 that any invention disclosed but not claimed in the reference was derived from the inventor of this application and is thus not an invention “by another”; (2) a showing of a date of invention for the claimed subject matter of the application which corresponds to subject matter disclosed but not claimed in the reference, prior to the effective U.S. filing date of the reference under 37 CFR 1.131(a); or (3) an oath or declaration under 37 CFR 1.131(c) stating that the application and reference are currently owned by the same party and that the inventor named in the application is the prior inventor under pre-AIA 35 U.S.C. 104 as in effect on March 15, 2013, together with a terminal disclaimer in accordance with 37 CFR 1.321(c). This rejection might also be overcome by showing that the reference is disqualified under pre-AIA 35 U.S.C. 103(c) as prior art in a rejection under pre-AIA 35 U.S.C. 103(a). See MPEP § 706.02(l)(1) and § 706.02(l)(2).
Claims 10, 15 and 17 are rejected under pre-AIA 35 U.S.C. 103(a) as being obvious over Rabuka et al. (US 20250152724).
The present application claims the elected species shown below:
PNG
media_image1.png
264
627
media_image1.png
Greyscale
.
The ‘724 publication teaches the following species:
PNG
media_image3.png
593
981
media_image3.png
Greyscale
, see page 86. Said compound is administered to react with a protein that has an aldehyde in a hydrazine-Pictet-Spengler ligation.
The main differences between the elected species and the cited compound are 1) Z1 is nitrogen versus Applicant’s carbon; and 2) the substitution on the phenyl ring of the indole ring, i.e. the linker and drug.
The ‘724 reference teaches the equivalency of nitrogen and carbon at the instant Z1, see page 15, paragraph [0191], formula (I).
The ‘724 reference also teaches the following species:
PNG
media_image4.png
112
657
media_image4.png
Greyscale
, see page 81. This is the exact substitution on the elected species on the phenyl ring that forms the indole ring system.
Since W1 and W2 of the present claims are defined as drugs, it would be obvious to replace one linker and drug for the other since the ‘724 reference teaches the equivalency of the linkers and drugs.
Thus, claims 10, 15 and 17 are obvious over Rabuka et al.
Claims 10, 15 and 17 are rejected under pre-AIA 35 U.S.C. 103(a) as being obvious over Yeo et al. (US 20250101098).
The present application claims the elected species shown below:
PNG
media_image1.png
264
627
media_image1.png
Greyscale
.
The ‘098 publication teaches the following species:
PNG
media_image5.png
617
877
media_image5.png
Greyscale
, see page 82. Said compound is administered to react with a protein that has an aldehyde in a hydrazine-Pictet-Spengler ligation.
The difference between the elected species and the cited compound is the substitution on the phenyl ring of the indole ring, i.e. the linker and drug.
The ‘098 reference also teaches the following species:
PNG
media_image4.png
112
657
media_image4.png
Greyscale
, see page 76. This is the exact substitution on the elected species on the phenyl ring that forms the indole ring system.
Since W1 and W2 of the present claims are defined as drugs, it would be obvious to replace one linker and drug for the other since the ‘724 reference teaches the equivalency of the linkers and drugs.
Thus, claims 10, 15 and 17 are obvious over Yeo et al.
Claims 10, 15 and 17 are rejected under pre-AIA 35 U.S.C. 103(a) as being obvious over Barfield et al. (US 20250121083) in view of Yeo et al. (US 20250101098).
The present application claims the elected species shown below:
PNG
media_image1.png
264
627
media_image1.png
Greyscale
.
The ‘0838 publication teaches the following species:
Claims 10, 15 and 17 are rejected under pre-AIA 35 U.S.C. 103(a) as being obvious over Chuprakov et al. (US 20240343818).
This rejection is similar to the first 103 rejection over Rabuka et al. The publication has similar compounds, and therefore, a similar rationale is equally applicable here.
Thus, claims 10, 15 and 17 are obvious over Chuprokov et al.
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 claims at issue 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); and 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 a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form 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 http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-17 and 35-37 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 9-53 and 63 of copending Application No. 18578690 (US 20250121083). Although the conflicting claims are not identical, they are not patentably distinct from each other because the claims in the ‘690 application are a subgenus of the present claims. See also the 103 rejection above which is equally applicable here.
This is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.
Claims 1-17 and 35-37 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-9 and 22-62 of copending Application No. 18291900 (US 20250152724). Although the conflicting claims are not identical, they are not patentably distinct from each other because the claims in the ‘900 application are a subgenus of the present claims. See also the 103 rejection above which is equally applicable here.
This is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.
Claims 1-17 and 35-37 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 9-53 and 63 of copending Application No. 18291897 (US 20250101098). Although the conflicting claims are not identical, they are not patentably distinct from each other because the claims in the ‘897 application are a subgenus of the present claims. See also the 103 rejection above which is equally applicable here.
This is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SUSANNA MOORE whose telephone number is (571)272-9046. The examiner can normally be reached Monday - Friday, 10:00 am to 7:00 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Murray can be reached on 571-272-9023. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SUSANNA MOORE/Primary Examiner, Art Unit 1624
Prosecution Insights