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 .
Application and Claims Status
Applicant’s preliminary amendments filed on July 19, 2024 are acknowledged and entered.
Claims 1-20 were pending. In the amendment as filed on July 19, 2024, applicants have amended no claims; cancelled claims 1-20; and added new claims 21-40. Therefore, claims 21-40 are currently pending.
Priority
The instant application is a nonprovisional application that claims domestic benefit of U.S. Provisional Application No. 63/387,235, filed 12/13/2022, and claims the benefit of the provisional application 63/597,871, filed 11/10/2023.
Information Disclosure Statement
The information disclosure statements (IDS) filed on 03/08/2024, 04/05/2024, 07/25/2024, 07/24/2025, 10/13/2025, and 10/20/2025 are in compliance with the provisions of 37 CFR 1.97. All references have been considered except where marked with a strikethrough. A signed copy of all Form 1449s are included with this Office Action.
The following document from the 03/08/2024 IDS was not considered, with the examiner explanation following:
Lu et al. Linkers having a Crucial Rose in Antibody-Drug Conjugates. Int J Mol Sci 17(4):561 (2016) – images within the document were smeared (Cite No. 078);
Last, for clarity, on the 03/08/2024 IDS, the Cite No. 136 should be authored as Robert E. Notari. It currently reads “WIDDER et al.”
Specification – Abstract
Applicant is reminded of the proper content of an abstract of the disclosure.
A patent abstract is a concise statement of the technical disclosure of the patent and should include that which is new in the art to which the invention pertains. The abstract should not refer to purported merits or speculative applications of the invention and should not compare the invention with the prior art.
If the patent is of a basic nature, the entire technical disclosure may be new in the art, and the abstract should be directed to the entire disclosure. If the patent is in the nature of an improvement in an old apparatus, process, product, or composition, the abstract should include the technical disclosure of the improvement. The abstract should also mention by way of example any preferred modifications or alternatives.
Where applicable, the abstract should include the following: (1) if a machine or apparatus, its organization and operation; (2) if an article, its method of making; (3) if a chemical compound, its identity and use; (4) if a mixture, its ingredients; (5) if a process, the steps.
Extensive mechanical and design details of an apparatus should not be included in the abstract. The abstract should be in narrative form and generally limited to a single paragraph within the range of 50 to 150 words in length.
See MPEP § 608.01(b) for guidelines for the preparation of patent abstracts.
Applicant is reminded of the proper content of an abstract of the disclosure.
In chemical patent abstracts for compounds or compositions, the general nature of the compound or composition should be given as well as its use, e.g., “The compounds are of the class of alkyl benzene sulfonyl ureas, useful as oral anti-diabetics.” Exemplification of a species could be illustrative of members of the class. For processes, the type of reaction, reagents and process conditions should be stated, generally illustrated by a single example unless variations are necessary.
The abstract of the disclosure is objected to because: it does not describe the general nature of the compound or composition; does not provide an exemplification of a genus or species; it includes the title of the application on the abstract page, as well. Examiner also notes the misspelling of “therapeutics”. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Specification – Drawings
The drawing is objected to because of the following informality:
The 115In isotope label in FIG. 2 is currently formatted as “115In-Compound 1 (100nm)” and examiner suggests that the numbering is superscripted to read “115In-Compound 1” as this follows the standard notation for isotopic formatting. Appropriate correction is required.
Specification – Disclosure
The disclosure is objected to because of the following informalities:
On page 1, para 0002, applicant writes “somatostatin subtype-2 receptor (SST2R).” This is incorrectly abbreviated, as it should be abbreviated SSTR2 instead. This error is repeatedly made throughout the application, including in the title. Appropriate correction is required.
On page 6, para 0018, applicant writes, “Thisnon-specific toxicity…” Examiner suggests, “This non-specific toxicity…” Appropriate correction is required.
On page 6, para 0020, applicant writes, “(SSTR1, SSTR2, SSTR2, SSTR4, SSTR5).” SSTR2 is repeated twice here. Appropriate correction is required.
On page 8, para 0026, applicant writes, “which areSST2R ligand drug conjugates.” Examiner suggests, “which are SST2R ligand drug conjugates.” Appropriate correction is required.
On page 17, under the heading “Spacer and Linkers,” the first embodiment is misappropriately identified as para 0001. It should properly be identified as para 0064. Appropriate correction is required.
On page 114, para 00289, applicant writes, “radionucleide” and examiner suggests appropriate spelling to “radionuclide.” Appropriate correction is required.
On page 124-125, para 00333, the applicant describes the synthesis and identity of Compound 1, as well as the identity of Compound 2, on page 127. Corresponding biological data is shown for Compound 1 and Compound 2 on page 217, Table 1. Applicant then goes on to describe improved internalization of ethylene diamine moiety over piperazine moiety on page 221, para 00388. In para 00389, applicant shows comparative compounds, Compound 1 and Compound 2. These Compounds 1 and 2 are not the same compounds as previously described on page 124-125 para 00333 and page 127. Appropriate correction is required.
The specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any of the errors of which applicant may become aware of in the specification.
Claim Objections
Claim 21 is objected to because of the following informality: “A compound that has the structure of Formula (A), or a pharmaceutically acceptable salt thereof” should be rewritten as “A compound of Formula (A), or a pharmaceutically acceptable salt thereof:”. Appropriate correction is required.
Claim 21 is objected to because of the following informality: the “-(CH2)C(Ra)=N-O-(CH2)-” should be replaced with “-CH2C(Ra)=N-O-CH2-” on page 2, in the definition of X1. Appropriate correction is required.
Claim 29 is objected to because of the following informalities: the “-N(R10)(unsubstituted or substituted benzyl)carbonoyl” should be rewritten as “-N(R10)(unsubstituted or substituted benzyl)carbonyl-“ on page 4, in the limitation of L2b, because “carbonyl” is misspelled. Further, the “.” should be removed on page 5, in the definition of w. Appropriate correction is required.
Claim 34 is objected to because of the following informality: the line “(maps to track one claim 3 but generically rather than as species)” should be altogether removed. To the examiner, it reads like the applicant’s internal notation or reminder was never removed from the submitted application. Appropriate correction is required.
Claim 36 is objected to because of the following informalities: on page 6, the phrase “or L1 is a spacer that is present and is -X2-L3-L4-“ should read, for clarity, “L1 is -X2-L3-L4-“. On page 6, in the limitation of L4b, applicant recites “C3C8cycloalkylene” which should read “C3-C8cycloalkylene”. Further, on page 7, in the definition of L4c, there is an extra space present in between the oxygen and nitrogen of “-O-, -NR10-“. Appropriate correction is required.
Claim 39 is objected to because of the following informality: there is an extra comma after the wherein statement that should be removed. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 21-40 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 21 is indefinite for the phrase “Rd is a payload moiety comprising a chemotherapeutic agent,” because one of ordinary skill in the art could not reasonably determine the metes and bounds of the claim. Specifically, it is unclear what structural limitations are placed on Rd from the phrase. One of ordinary skill in the art would reasonably read the phrase as “an agent sufficiently cytotoxic to cancer cells,” but it is unclear what bounds are set on the compound’s structure from this functional limitation. Applicant does provide embodiments of acceptable chemotherapeutic agents for the Rd position (instant specification, page 16-17, para 00063) but the six embodiments are only a tiny fraction of the chemical space that would satisfy this functional limitation. Furthermore, there are certainly compounds of unknown structure, or even of known structure that satisfy the limitation of being a “chemotherapeutic agent,” unbeknownst to the current scientific literature.
As the full metes and bounds of the structure of Formula (A) are unclear from the phrase, “Rd is a payload moiety comprising a chemotherapeutic agent,” claim 21, and subsequently its dependent claims 22-39, are indefinite.
Claims 21 recites that “L is -L1-L2-“ and further recites “L1 is an optional spacer” and “L2 is an optional linker.” The inventor or joint inventor should note that claim 21 is a reach-through claim. The claim attempts to obtain protection for subject matter that is prophetic and/or has yet to be invented, including any linker that has not yet been invented. Similarly, the metes and bounds of a “linker group” are not defined by the claim, the specification does not provide an adequate standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the metes and bounds of the invention. The specification, on pages 17-96, para [0064]-[0096], teaches numerous, nonlimiting embodiments of linker groups. However, neither the specification, nor the claim, explicitly limits the invention to any specifically disclosed or recited embodiments of linker groups. Consequently, the compound of Formula (A) comprising a “linker group” has been rendered indefinite by the use of the reach-through protocol.
Claims 22-29 are rejected as being dependent upon claim 21 and failing to give structure to L.
Claim 21 is vague and indefinite for the limitation “or when both Ra and Rb are present then Ra and Rb are taken together with the intervening atoms to which they are attached to form a piperidine or pyrrolidine.” According to claim 21, the Ra species is used in X1, which can be “-N(Ra)-, -O-, -C(=O)-, -C(=O)N(Ra)-, -S(=O)-, -(CH2)C(Ra)=N-O-(CH2)-“. If Ra is present as “-N(Ra)-“, then this limitation is clear: the intervening atoms can possibly form a piperidine or pyrrolidine ring. However, if Ra is present as “-C(=O)N(Ra)-“ or “-(CH2)C(Ra)=N-O-(CH2)-“, then the intervening atoms to which Ra and Rb are attached will not form a piperidine or a pyrrolidine.
Claim 21 lacks proper antecedent basis in its recitation of “the structure”.
Claim 29 and claims dependent thereon are rejected because claim 21 recites the limitation “L2b is absent, -N(R10)(unsubstituted or substituted benzyl)carbamate, -N(R10)(unsubstituted or substituted benzyl)carbonoyl, or -N(R10)(unsubstituted or substituted benzyloxy).” However, R10 is not defined in this claim or the claim from which it depends, claim 21. R10 is first defined in claim 36. Therefore, claim 29 lacks proper antecedent basis.
Claim 29 and claims dependent thereon are rejected as vague and indefinite because: L2 is defined as “-(L2a)w-L2b- or -L2c-“. Further “L2b is absent, -N(R10)(unsubstituted or substituted benzyl)carbamate, -N(R10)(unsubstituted or substituted benzyl)carbonoyl, or -N(R10)(unsubstituted or substituted benzyloxy).” If -L2b- is already substituted twice—once to L2a- and once to Rd—then if L2b is -N(R10)(unsubstituted or substituted benzyl)carbamate, for instance, the nitrogen will have a total of four substituents, making it a quaternary ammonium salt. The applicant does not provide support in the specification or claims that these are the compounds for which protection is sought. Therefore, claim 29 is vague and indefinite.
The claims 29 and 36 include limitations of “each R12 is independently selected from hydrogen, C4-C20polyethylene glycol” for claim 29, “R13 is independently selected from C4-C20polyethylene glycol and C4-C20polyethyleneglycol-NH2” for claim 29, and ”C1-C10alkylene, unsubstituted or substituted C1-C10heteroalkylene, C4-C20polyethylene glycol” for claim 36, which are indefinite because either there is no closed definition provided in the specification, or because the definition provided includes so many variations that one skilled in the art would not be able to envision the possible variations of Formula (A) included in the scope of the claims. “[A] Markush group may be so expansive that persons skilled in the art cannot determine the metes and bounds of the claimed invention. For example, if a claim defines a chemical compound using one or more Markush groups, and that claim encompasses a massive number of distinct alternative members, the claim may be indefinite under 35 U.S.C. 112(b) if one skilled in the art cannot determine its metes and bounds due to an inability to envision all of the compounds defined by the Markush group(s). In such a circumstance, a rejection of the claim for indefiniteness under 35 U.S.C. 112(b) is appropriate.” See MPEP 2173.05(h). “Polyethylene” is not explicitly defined in the specification, but both “alkyl” and “alkylene” are defined on page 119, para 00305 and 00306, respectively, as referring to, in the case of alkyl, an aliphatic straight or branched chain that has a numerical range of 1 to 10 carbons, or in the case of alkylene, a divalent alkyl radical. Accordingly, a C1-C10alkyl alone includes many different variations owing to the broad definition, but the applicant goes further and claims C4-C20polyethylene glycol and C4-C20polyethyleneglycol-NH2. The scope of possible variations of C1-C10alkylene, C1-C10heteroalkylene, C4-C20polyethylene glycol and C4-C20polyethyleneglycol-NH2 is thus enormous and the limitation indefinite for the reasons cited above. Applicant could make the claims definite by, for instance, amending the claims to recite specific alkylene, heteroalkylene, polyethylene glycol, polyethyleneglycol-NH2 groups included in the scope of the claims.
Claim 32 is vague and indefinite because it is unclear what coverage the term -(L2a)w- is claiming. L2a is limited to natural or unnatural amino acids (as defined in claim 31) and w is 1, 2, 3, 4, 5, or 6 (as defined in claim 29). In instant claim 32, applicant claims -(L2a)w is -valine-citrulline, as an example. Is the applicant suggesting that w = 2 because there is one valine amino acid and one citrulline amino acid, in this example, or rather that the valine-citrulline unit can be repeated “w” number of times (up to 6 repeating units), and are therefore claiming a string of amino acids, such as, in the instance of w = 6, valine-citrulline-valine-citrulline-valine-citrulline-valine-citrulline- valine-citrulline-valine-citrulline?
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Scope of Enablement - Compounds
Claims 21-39 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 following:
A compound of Formula (A) (as recited in Claim 21)
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or a pharmaceutically acceptable salt thereof,
where A is NH, O;
where R1, R3, Ra, Rb are H;
where R2 is H, C1-C3alkyl;
where R8, R9 are H, C1-C3alkyl, C1-C3fluoroalkyl, substituted or unsubstituted C1-C3heteroalkyl;
where R4 and R5 are H, halogen, C1-C3alkyl, C1-C3fluoroalkyl, CN, OR8, N(R8)2;
where R6 and R7 are H, halogen, C1-C3alkyl, C1-C3fluoroalkyl, substituted or unsubstituted C1-C3heteroalkyl, CN, OR8, N(R8)2, SR8, C(=O)N(R8)2;
where m, n = 1;
where Rc is as defined in claim 21;
where Pd are the chemotherapeutic agents recited in Claim 39;
where L is as defined in claim 21 and dependent claims 29-38;
does not reasonably provide enablement for elements that are outside the scope of the enabling elements listed above. 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 the invention commensurate in scope with these claims.
To be enabling, the specification of the patent application 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 (Fd. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996). As pointed out by the court in In re Angstadt, 537 F.2d 498 at 504 (CCPA 1976), the key word is "undue", not "experimentation".
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls. 1986) at 547 the court recited eight factors:
1- the quantity of experimentation necessary,
2- the amount of direction or guidance provided,
3- the presence or absence of working examples,
4- the nature of the invention,
5- the state of the prior art,
6- the relative skill of those in the art,
7- the predictability of the art, and
8- the breadth of the claims
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
The nature of the invention:
The nature of the invention relates to compounds of Formula (A) in claim 21. Such compounds are useful as small molecule drug conjugates (SMDCs). This invention is also directed to a method for the treatment of cancer comprising administering said compounds.
Predictability of the art:
The compounds synthesized in the instant specification appear novel. However, the hypothetical compounds in claim 21 would be unpredictable in terms of one skilled in the art being able to synthesize every possible compound claimed in instant claim 21. It is well established that “the scope of enablement varies inversely with the degree of unpredictability of the factors involved,” and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
In terms of the law, MPEP 2107.03 states “evidence of pharmacological or other biological activity of a compound will be relevant to an asserted therapeutic use if there is a reasonable correlation between the activity in question and the asserted utility. Cross v. Iizuka, 753 F.2d 1040, 224 USPQ 739 (Fed. Cir. 1985); In re Jolles, 628 F.2d 1322, 206 USPQ 885 (CCPA 1980); Nelson v. Bowler, 626 F.2d 853, 206 USPQ 881 (CCPA 1980).” If correlation is lacking, it cannot be relied upon, Ex parte Powers, 220 USPQ 924; Rey-Bellet and Spiegelberg v. Engelhardt v. Schindler, 181 USPQ 453; Knapp v. Anderson, 177 USPQ 688. Indeed, the correlation must have been established “at the time the tests were performed”, Hoffman v. Klaus, 9 USPQ2d 1657.
Level of skill in the art:
An ordinary artisan in the area of drug development would have experience in synthesizing and screening chemical compounds for particular activities, such as a medical doctor or chemist. Screening of new drug candidates, while complex, is routine in the art. The process of finding new drugs that have in vitro activity against a particular biological target, (i.e., receptor, enzyme, etc.) is well known. Additionally, while high throughput screening assays can often be employed, developing a therapeutic method, as claimed, is generally not well-known or routine, given the complexity of certain biological systems.
The breadth of the claims:
The scope of the claims involves compounds of Formula (A), shown below.
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Claim 21 is very broad in the number of variables and the options of substituents for each variable. There is an extremely large amount of hypothetical compounds included in claim 21.
The amount of direction provided, the presence or absence of working examples, and the quantity of experimentation necessary:
The specification provides the synthesis of 7 compounds and biological and LCMS data for 159 compounds.
Synthesis methods are not taught in the specification to provide for the aforementioned variables to include all of the possible substituents listed in the claims. For example, the number of possibilities encompassed by the claim language for Linker L is enormous. As an example of a possibility based on the claims, there is no working example of a linker L that is: L1 spacer of 6 amino acids (X2, p), attached to a C10heteroalkylene (L3), attached to a substituted C3-C8cycloalkylene (L4), attached to linker L2, which further comprises the possibility of 6 unnatural amino acids (L2a, w) attached to -N(R10)(unsubstituted or substituted benzyl)carbamate (L2b), with the benzyl substituted with NHR12, where R12 is C20polyethylene glycol. In another example demonstrating a lack of enablement, there are no working examples where “R2 and R3 are taken together with the intervening atoms to which they are attached to form a morpholine;” as recited in claim 21. It would require one skilled in the art, such as a chemist, to perform thousands of reactions to determine which compounds of Formula (A) can be prepared and would likely require synthesis methods other than those provided in the specification. This is undue experimentation given the limited guidance and direction provided by Applicants.
Accordingly, the instant claims do not comply with the enablement requirement of 35 U.S.C. 112(a), since to practice the claimed invention a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
Claims 22-39, which are dependent on claim 21, are also rejected for further requiring and/or reciting elements that are outside the scope of the enabling elements listed above.
Scope of Enablement – Cancer
Claim 40 is 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 non-small cell lung cancer does not reasonably provide enablement for treating cancer generally. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, "The Federal Circuit has repeatedly held that "the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation." In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)" (emphasis added). The "make and use the full scope of the invention without undue experimentation" language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: "A lack of enablement for the full scope of a claim, however, is a legitimate rejection." The principle was explicitly affirmed most recently in 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).
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.
The treatment of cancer generally cannot possibly be considered enabled.
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.
The analysis is as follows:
1) Breadth of claims.
"Cancer" is not a single disease, or cluster of closely related disorders. There are hundreds of cancers, which have in common only some loss of controlled cell growth. Cancers are highly heterogeneous at both the molecular and clinical level, something seen especially in, for example, the cancers of the breast, brain and salivary glands. They can occur in pretty much every part of the body. To be able to simply stop cancer cells generally from being able to proliferate. Many of these approaches --- and there have been others as well --- have produced anti-cancer drugs. However, despite high hopes for success, and a plausible theory why these should work for cancers generally, none of these approaches have ever produced a drug which come remotely near such a goal.
Specifically, the prior art knows that there never has been a compound capable of treating cancers generally. "The cancer therapy art remains highly unpredictable, and no example exists for efficacy of a single product against tumors generally." A similar statement appears at In re Application of Hozumi et al., 226 USPQ 353: "In spite of the vast expenditure of human and capital resources in recent years, no one drug has been found which is effective in treating all types of cancer. Cancer is not a simple disease, nor is it even a single disease, but a complex of a multitude of different entities, each behaving in a different way". There are compounds that treat a modest range of cancers, but no one has ever been able to figure out how to get a compound to be effective against cancer generally, or even a majority of cancers.
The attempts to find compounds to treat the various cancers arguably constitute the single most massive enterprise in all of pharmacology. This has not resulted in finding any treatment for tumors generally. Indeed, the existence of such a "silver bullet" is contrary to our present understanding in oncology. This is because it is now understood that there is no "master switch" for cancers generally; cancers arise from a bewildering variety of differing mechanisms. Even the most broadly effective antitumor agents are only effective against a small fraction of the vast number of different cancers known. This is true in part because cancers arise from a wide variety of sources, primarily a wide variety of failures of the body's cell growth regulatory mechanisms, but also such external factors such as viruses (an estimated at least 20% are of viral origin e.g. Human papillomavirus, EBV, Hepatitis B and C, HHV-8, HTLV-1 and other retroviruses, and quite possibly Merkel cell polyomavirus, and there is some evidence that CMV is a causative agent in glioblastoma), exposure to chemicals such as tobacco tars, excess alcohol consumption (which causes hepatic cirrhosis, an important cause of HCC), ionizing radiation, and unknown environment factors.
Accordingly, there is substantive "reason for one skilled in the art to question the objective truth of the statement of utility or its scope" (In re Langer, 183 USPQ 288, 297), specifically, the scope of covering cancer generally.
Similarly, In re Novak, 134 USPQ 335, 337-338, says "unless one with ordinary skill in the art would accept those allegations as obviously valid and correct, it is proper for the examiner to ask for evidence which substantiates them." There is no such evidence in this case. Likewise, In re Cortright, 49 USPQ2d 1464, states: "Moreover, we have not been shown that one of ordinary skill would necessarily conclude from the information expressly disclosed by the written description that the active ingredient" does what the specification surmises that it does. That is exactly the case here. Moreover, even if applicants' assertion that cancer in general could be treated with these compounds were plausible --- which it is not ---, that "plausible" would not suffice, as was stated in Rasmusson v. SmithKline Beecham Corp., 75 USPQ2d 1297, 1301: "If mere plausibility were the test for enablement under section 112, applicants could obtain patent rights to "inventions" consisting of little more than respectable guesses as to the likelihood of their success."
Different types of cancers affect different organs and have different methods of growth and harm to the body, and different vulnerabilities. The skill thus depends on the particular cancer involved. There are some cancers where the chemotherapy skill level is high and there are multiple successful chemotherapeutic treatments. The mechanism in these situations, however, is not necessarily the same as is alleged for these compounds.
One skilled in the art knows that chemotherapy of brain tumors is especially difficult. This is because 1) the blood-brain barrier, which is often intact in parts or all of a brain tumor, will block out many drugs, as it is the purpose of the blood-brain barrier to protect the brain from alien chemicals, and 2) CNS tumors are characterized by marked heterogeneity, which greatly decreases vulnerability to chemotherapy. As a result, many categories of CNS tumors simply have no chemotherapy available. These include, generally, hemangioblastomas, meningiomas, craniopharyngiomas, acoustic neuromas, pituitary adenomas, optic nerve gliomas, glomus jugulare tumors and chordomas, to name just some. With regard to gliomas, GBM is considered untreatable; no effective agents have emerged for the treatment of GBM, despite 20 years of enrolling patients in clinical trials. It is radiation and surgery which are used for low grade gliomas (e.g. pilocytic astrocytoma and diffuse astrocytomas), as no drug has been found effective. There is no drug treatment established as effective for optic nerve gliomas or gangliogliomas. Indeed, very few gliomas of any type are treated with pharmaceuticals; it is one of the categories of cancer that is the least responsive to drugs.
Lymphomas of the stomach are not commonly treated with anti-cancer agents per se, but instead, surgery or radiation and antibiotic therapy (e.g. amoxicillin, metronidazole, bismuth, and omeprazole) are the primary treatments.
Neuroendocrine tumors of the cervix generally do not respond to chemotherapy.
A number of sarcomas, including alveolar soft part sarcoma (ASPS), retroperitoneal sarcoma, most liposarcomas, and the assorted chondrosarcomas, are generally considered not to respond to chemotherapy; no chemotherapeutic agent has been established as effective.
It is important to note that tumors can 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 actinomycin D and vincristine. Such drugs are never used with clear cell renal carcinoma, which is treated, although without much success, with immunotherapy using the cytokines interleukin-2 and interferon-alpha. 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. 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 scope of treating inflammation generally is extraordinarily broad. Inflammation is a process which can take place in virtually any part of the body. There is a vast range of forms that it can take, causes for the problem, and biochemical pathways that mediate the inflammatory reaction. It is one of the most pervasive of all body processes. Inflammation is a very general term which encompasses a huge variety of specific processes.
2) The nature of the invention and predictability in the art.
With specific reference to cancer, Ex parte Kranz, 19 USPQ2d 1216, 1219 notes the "general unpredictability of the field [of] …anti-cancer treatment." In re Application of Hozumi et al., 226 USPQ 353 notes the "fact that the art of cancer chemotherapy is highly unpredictable". More generally, the invention is directed toward medicine and is therefore physiological in nature. It is well established that "the scope of enablement varies inversely with the degree of unpredictability of the factors involved," and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
3) State of the Prior Art. The claimed compounds are of Formula (A). As far as the examiner is aware, these compounds have not been successfully used as broad range anticancer agents.
4) Working Examples. Applicants have provided no working examples which are successfully used as broad range anticancer agents. Applicants have, however, contemplated the treatment of the following broad range of cancers: anal cancer, bladder cancer, bowel cancer, brain cancer, breast cancer, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, gallbladder cancer, gastric cancer, heart cancer, kidney cancer, lung cancer, liver cancer, melanoma, uterine cancer, lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, thymus cancer, pheochromocytoma, medullary thyroid carcinoma, head & neck cancer, melanoma, or endocrine cancer (specification page 4-5, para 0011). However, the applicant only provides working examples of testing their claimed compounds against the NCI-H524 (ATCC) human small cell lung cancer cell line: Example K (page 216-217, para 00387) and Table 1 (page 217-220) shows data for each compound of the invention and its ability to inhibit cell proliferation in NCI-H524 cells. Thus, the claims provide enablement for the treatment for non-small cell lung cancer, but does not provide any data demonstrating the treatment of cancers broadly.
5) Skill of those in the art. Many, many mechanisms have been proposed over the decades as methods of treating the assorted cancers generally. Cytotoxic agents could be applied directly to the tumors cells, directly killing them. Immunotherapy involves stimulating the patient's immune system to attack cancer cells generally, either by immunization of the patient, in which case the patient's own immune system is trained to recognize tumor cells as targets, or by the administration of therapeutic antibodies as drugs, so the patient's immune system is recruited to destroy tumor cells by the therapeutic antibodies. Another approach would be to increase the amount or activity of the body's tumor suppressor genes, e.g. p53, PTEN, APC and CD95, which can for example activate DNA repair proteins, suppress the Akt/PKB signaling pathway, or initiate apoptosis of cancer cells. The angiogenesis inhibitor strategy was based on cutting off the blood supply that growing tumors need by shutting off the growth of new blood vessels by, for example, suppressing proliferation of endothelial cells or inducing apoptosis of endothelial cells. There is also the cancer stem cell paradigm, which hypothesizes that cancer could be treated generally, either by targeting the cancer stem cells themselves, or by targeting the epithelial-to-mesenchymal transition which supposedly generates the cancer stem cells. Yet another approach is to inhibit one or more of the assorted HSP90 proteins, which will supposedly disrupt the proper folding of signaling proteins that all cancers rely on. Inhibiting telomerase was said to be able to be able to simply stop cancer cells generally from being able to proliferate. Many of these approaches --- and there have been others as well --- have produced anti-cancer drugs. However, despite high hopes for success, and a plausible theory why these should work for cancers generally, none of these approaches have ever produced a drug which come remotely near such a goal.
Accordingly, there is substantive "reason for one skilled in the art to question the objective truth of the statement of utility or its scope" (In re Langer, 183 USPQ 288, 297), specifically, the scope of covering cancer generally. Moreover, even if applicants' assertion that cancer in general could be treated with these compounds were plausible --- which it is not ---, that "plausible" would not suffice, as was stated in Rasmusson v. SmithKline Beecham Corp., 75 USPQ2d 1297, 1301: "If mere plausibility were the test for enablement under section 112, applicants could obtain patent rights to "inventions" consisting of little more than respectable guesses as to the likelihood of their success."
6) Scope of the claims. The scope of the claim a method for the treatment of cancer comprising administering to a mammal with cancer an effective amount of a compound of claim 21, or a pharmaceutically acceptable salt thereof. Thus, the scope of the claim is very broad.
7) The quantity of experimentation needed. Given the fact that, historically, the development of new cancers drugs has been difficult and time consuming, and especially in view of factors 1 and 4 and 6, the quantity of experimentation needed is expected to be great.
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)." That conclusion is clearly justified here.
Scope of Enablement - Prevention
Claim 40 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AlA), first paragraph, because the specification, while being enabling for treatment, does not reasonably provide enablement for prevention. 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.
The following Wands factors have been considered if not explicitly discussed: (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.
The term “treatment” is defined on page 124, para 00331 of the instant specification and said definition also embraces prevention. The applicant writes “The terms ‘treat,’ ‘treating" or ‘treatment,’ as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms…or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.”
It is presumed “prevention” of the claimed condition would require a method of identifying those individuals who will develop the claimed condition before they exhibit symptoms.
The factors to be considered in making an enablement rejection were summarized above. 1) Preventing cancer requires identifying those patients who will acquire the condition before the symptoms occur. This would require extensive and potentially open-ended clinical research on healthy subjects. 2) There is no working example of such a preventive procedure in man or animal in the specification. 4) The claims rejected are drawn to clinical pharmacology and are therefore physiological in nature. 5) The state of the art is that no general procedure is art-recognized for determining which patients generally will develop cancer before the fact. 6) The artisan using applicants’ invention would be a Board Certified physician. Despite intensive efforts, pharmaceutical science has been unable to find a way of getting a compound to be effective for the prevention of cancer. Under such circumstances, it is proper for the PTO to require evidence that such an unprecedented feat has actually been accomplished, In re Ferens, 163 USPQ 609. No such evidence has been presented in this case. The failure of skilled scientists to achieve a goal is substantial evidence that achieving such a goal is beyond the skill of practitioners in that art, Genentech vs. Novo Nordisk, 42 USPQ2nd 1001, 1006. This establishes that it is not reasonable for any agent to be able to prevent cancer. 7) It is well established that "the scope of enablement varies inversely with the degree of unpredictability of the factors involved" and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). 8) The claims broadly read on all patients, not just those undergoing therapy for the claimed conditions.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 21-40 are rejected on the ground of nonstatutory double patenting as being unpatentable over Claims 1, 27-29 of U.S. Patent No. 12,134,610 B2. Although the claims at issue are not identical, they are not patentably distinct from each other. For example, the instant application teaches a compound of Formula (A), wherein A is NH, X1 is N(Ra), Ra is H, Rb is H, R1 is H, R2 is H, R3 is H, R4 is a halogen, R5 is CH3, m is 1, n is 1, L is -L1-L2- which are both an optional spacer and linker, respectively, R7 is H, R6 is H, Rd is a payload moiety comprising a chemotherapeutic agent (like monomethyl auristatin E), and Rc is
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These features are all identically taught in reference Claim 1. Furthermore, instant Claim 40 is directed towards a method for the treatment of cancer comprising administering to a mammal with cancer an effective amount of the claimed compound. Similarly, reference Claims 27-29 are directed towards a method for the treatment of cancer comprising administering to a mammal with cancer an effective amount of the same claimed compounds.
Claims 21-40 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 55, 73 of copending Application No. 19/232,304 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other. For example, the instant application teaches a compound of Formula (A), wherein A is NH, X1 is N(Ra), Ra is H, Rb is H, R1 is H, R2 is H, R3 is H, R4 is a CH3, R5 is H, m is 1, n is 1, L is -L1-L2-, L1 is a spacer, L2 is (L2a)w-L2b-, L2a is a natural or unnatural amino acid, w = 2, L2b is -N(R10)(unsubstituted or substituted benzyl)carbamate, R10 is H, R6 is H, R7 is H, Rd is a payload moiety comprising a chemotherapeutic agent (like monomethyl auristatin E), and Rc is
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These features are all identically taught in reference Claim 1, where Y is CH, Z is CR10, R10 is H, R9 is H, Ra is H, R1 is H, R2 is H, R3 is CH3, n is 1, L is -L1-L2-, R4 is H, R5 is H, J is NR6, R6 is H, Rd is the residue of a bioactive molecule of the formula Rd-H (like monomethyl auristatin E), spacer is a spacer, (A)w is an natural or unnatural amino acid, w = 2, R7 is H, R8 is H, and RA is
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Furthermore, instant Claim 40 is directed towards a method for the treatment of cancer comprising administering to a mammal with cancer an effective amount of the claimed compound. Similarly, reference Claim 73 is directed towards a method for the treatment of cancer comprising administering to a mammal with cancer an effective amount of the same claimed compounds. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
All claims are rejected.
No claims are allowed.
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/L.A.B./Examiner, Art Unit 1624
/JEFFREY H MURRAY/Supervisory Patent Examiner, Art Unit 1624