DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
Examiner acknowledges that, according to the Filing receipt received 01/27/2026, that the instant application 18/547,018 filed 08/18/2023 is a 371 of PCT/EP2022/053580 filed 02/15/2022 which claims foreign priority of EPO application EP21158130.1 filed 02/19/2021.
Information Disclosure Statement
The Information Disclosure Statement filed on 11/02/2023 is in compliance with the provisions of 37 CFR 1.97 and has been considered in full. A signed copy of list of references cited from the IDS is included with this Office Action.
Claim Objections
Claim 9 is objected to because of the following informalities: "FAP inhibitor.," should read "FAP inhibitor,". Appropriate correction is required.
Drawings
The drawings are objected to as failing to comply with 37 CFR 1.84(p)(5) because they include the following figure not mentioned in the description: Figure 3. Corrected drawing sheets in compliance with 37 CFR 1.121(d), or amendment to the specification to add the reference character(s) in the description in compliance with 37 CFR 1.121(b) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-4 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature without significantly more. The claim(s) recite(s) a cryptophycin compound of formula (I). The broadest reasonable interpretation of the claims includes cryptophycin compounds found in nature. As disclosed by Golakoti et al. (J. Am. Chem. Soc.; 1995), Cryptophycin 1 and Cryptophycin 2 are cryptophycins isolated from Nostoc sp. GSV 224, a species of cyanobacteria (p. 12030-12031). These compounds have the following structures (p. 12031).
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Golakoti et al. additionally discloses 18 new cryptophycins isolated from Nostoc sp. GSV 224 including the following (p. 12032, Chart 1).
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These compounds all fall within the scope of formula (I) and are known in the art to be naturally occurring. More of such compounds may be known in the art that are not depicted above. Per MPEP 2106, Step 1 of the subject matter eligibility tests asks whether the claimed invention is directed toward one of the four statutory categories. In the instant case, the compound is an article of manufacture and Step 1 is satisfied. However, moving to Step 2A (prong one), the claimed compounds are directed toward a judicial exception (product of nature). Per Step 2A (prong two), this judicial exception is not integrated into a practical application because the claims are directed toward the compounds themselves and the compounds are not merely included or recited. Finally, as in Step 2B, the claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because no additional elements are recited. Furthermore, while the claims are directed toward a genus that may read on compounds not found in nature, the scope of the claims still encompasses natural products. Examiner recommends that Applicant amend claims 1-4 such that the claimed genus does not read on any cryptophycin compounds found in nature (not limited to those depicted above).
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-8 and 11-14 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 1 recites “one of R6 and R8 represents… and the other is”. However, R6 is only present when X is NR6. It is unclear, if X is O, what R8 can be. Clarification is required. Claims 2-4 do not clarify the limitation at issue and are also rejected.
Claim 1 recites “a (C1-C6)alk(en)yl group”. It is unclear what moiety “alk(en)yl” is intended to represent. Clarification is required. Claims 2-4 do not clarify the limitation at issue and are also rejected.
Claims 1, 5, and 7 recite broader limitations followed by narrower limitations separated by the term “preferably”. The claim(s) are considered indefinite because there is a question or doubt as to whether the features introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Claims 2-4, 6, 8, and 11-14 either recite or incorporate the language at issue and are also rejected.
Claims 1, 5, and 7 recite “one or more substituents of the phenyl nucleus selected”. The limitation “the phenyl nucleus selected” lacks antecedent basis. Examiner suggests amending to “one or more substituents independently selected from”. Claims 2-4, 6, 8, and 11-14 either recite or require the limitation at issue and are also rejected.
Claims 1, 5, and 7 set forth alternatives for R6, R8, and/or R9 with a positive charge. However, no counter ion is set forth such that the claimed “compound” has a neutral charge. The scope of the claims is unclear as a compound, stereoisomer, or pharmaceutically acceptable salt thereof would all require a net zero charge. Claims 2-4, 6, 8, and 11-14 either recite or require the limitation at issue and are also rejected.
Claim 4 recites “chlorine, atom,”. It is unclear what “atom” encompasses. Clarification is required.
Claims 5 and 7 recite multiple definitions for the variable “n”. For example, “n is an integer of 1 to 20” and “n = 3 to 50” and “n = 3 to 20”. This causes confusion as the definition of the same variable changes throughout the structure. Clarification is required. Claims 6, 8, and 11-14 either recite or require the limitation at issue and are also rejected.
Claim 5 recites “N-maleimide”. It is unclear whether this term refers to “maleimide” or “N-methylmaleimide” as “N-maleimide” does not denote a structure known in the art. Clarification is requested. Claims 6 and 13 are also rejected for not clarifying the limitation at issue.
Claim 7 recites “the coupling reaction with RCG2 of Ab”. This limitation lacks antecedent basis. Claim 7 additionally recites “a residue of reactive coupling group RCG1” but no definition of RCG1 is set forth in independent claim 7. This limitation also lacks antecedent basis. Examiner suggests correction to “G represents a residue selected from:”. Claims 8, 11-12, and 14 require the limitation at issue and are also rejected.
Claim 8 recites “the N+(CH3)2 group in formula (IV.1)”. This limitation lacks antecedent basis because formula (IV.1) is not set forth in claim 8 or claim 7, from which claim 8 depends. Does applicant mean “formula (V.1)”?
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 5-6 and 13 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a cryptophycin derivative of formula (II) wherein L is of formula Str-Pep-Sp, wherein Pep is a bond, a non-peptide chemical moiety selected from those listed in claim 5, or a peptidyl moiety as depicted in claim 6 options (iii) or (iv), does not reasonably provide enablement for a cryptophycin derivative of formula (II) wherein L is a bivalent organic linker with a molecular weight up to 1000 generally and/or a peptidyl moiety 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 make the invention commensurate in scope with these claims.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the application coupled with information known in the art without undue experimentation. (United States v. Teletronics Inc., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is needed is not based on a single factor, but rather a conclusion reached by weighing many factors (See Ex parte Forman 230 USPQ 546 (Bd. Pat. App. & Inter. 1986) and In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988).
These factors include the following:
1) Amount of guidance provided by applicant. Applicant has demonstrated within the application how to make compounds and compositions of formula (II). However, the instant specification provides no species of formula (II) wherein the Pep group of L is broader than the subgenuses of claim 6 as below (circled by Examiner). Examiner notes that the working examples do include species within the scope of Sp as depicted in claim 5.
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Furthermore, the examples in the specification are only so broad as to describe a genus wherein L is of the formula Str-Pep-Sp. No working examples exist of any compounds with differing connectivity from that above, or any other substituents or groups as previously mentioned. As was stated in Morton International Inc. v. Cardinal Chemical Co., 28 USPQ2d 1190 “The specification purports to teach, with over fifty examples, the preparation of the claimed compounds with the required connectivity. However...there is no evidence that such compounds exist...the examples of the '881 patent do not produce the postulated compounds...there is...no evidence that such compounds even exist.” The same circumstance appears to be true here. Hence, Applicants must show that these compounds can be made, or limit the claims accordingly.
2) The nature of the invention and predictability in the art. The invention is directed toward cryptophycin derivatives and conjugates thereof. Regarding predictability in the art, chemistry is generally regarded as unpredictable. See In Re Marzocchi and Horton, 169 USPQ at 367 paragraph 3:
“Most non-chemists would probably be horrified if they were to learn how
many attempted syntheses fail, and how inefficient research chemists are.
The ratio of successful to unsuccessful chemical experiments in a normal
research laboratory is far below unity, and synthetic research chemists, in
the same way as most scientists, spend most of their time working out
what went wrong, and why. Despite the many pitfalls lurking in organic
synthesis, most organic chemistry textbooks and research articles do give
the impression that organic reactions just proceed smoothly and that the
total synthesis of complex natural products, for instance, is maybe a labor-
intensive but otherwise undemanding task. In fact, most syntheses of
structurally complex natural products are the result of several years of
hard work by a team of chemists, with almost every step requiring careful
optimization. The final synthesis usually looks quite different from that
originally planned, because of unexpected difficulties encountered in the initially chosen synthetic sequence. Only the seasoned practitioner who
has experienced for himself the many failures and frustrations which the
development (sometimes even the repetition) of a synthesis usually
implies will be able to appraise such work ......Chemists tend not to publish
negative results, because these are, as opposed to positive results, never
definite (and far too copious)...” Dorwald F. A. Side Reactions in Organic
Synthesis, 2005, Wiley: VCH, Weinheim pg. IX of Preface.
The scope of any compounds, compositions, or pharmaceutically acceptable salts where the variables were not those mentioned above are not adequately enabled or defined. Applicants provide to guidance as how the compounds are made.
3) Number of working examples. The compound core depicted with specific substituents as above represents a narrow subgenus for which Applicant has provided sufficient guidance to make and use; however, this disclosure is not sufficient to allow extrapolation of the limited examples to enable the scope of the compounds instantly claimed. Applicant has provided no working examples of any compounds, compositions, or pharmaceutically acceptable salts where the variables were not those mentioned above.
Within the specification, “specific operative embodiments or examples of the invention must be set forth, Examples and description should be of sufficient scope as to justify the scope of the claims, Markush claims must be provided with support in the disclosure for each member of the Markush group. Where the constitution and formula of a chemical compound is stated only as a probability or speculation, the disclosure is not sufficient to support claims identifying the compound by such composition or formula.” See MPEP 608.01(p).
4) Scope of the claims. The scope of the claims is all of the millions of possible compounds represented by general formula (II).
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Given the number of moieties within the scope of L (“a linker group selected from bivalent organic groups having a molecular weight of up to 1000”; “Pep is a… peptidyl moiety”) the claims are incredibly broad.
5) Level of skill in the art. The artisan using Applicant’s invention would be a chemist with a Ph.D. degree and having several years of bench experience.
6) Undue experimentation. 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)."
The conclusion is clearly justified here that Applicant is not enabled for making these compounds or compositions.
Claims 7-8, 11-12, and 14 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a cryptophycin conjugate of formula (III) wherein L is of formula Str-Pep-Sp, wherein Pep is a bond, a non-peptide chemical moiety selected from those listed in claim 7, or a peptidyl moiety as depicted in claim 8 and wherein Ab is folic acid, DUPA (Glu-urea-Glu), acetazolamide, or a FAP inhibitor selected from UAMC1110, N-(4-quinolynoyl)-Gly(2-cyanopyrrolidines), FAPI-04, and sibrotumzumab, does not reasonably provide enablement for a cryptophycin conjugate of formula (III) wherein L is a bivalent organic linker with a molecular weight up to 1000 generally and/or a peptidyl moiety generally, and Ab is an oligopeptide or polypeptide generally, an antibody or antibody-like molecule generally, a small organic group having a molecular weight of 750 or lower generally, an analog of acetazolamide, or a FAP inhibitor 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 make the invention commensurate in scope with these claims.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the application coupled with information known in the art without undue experimentation. (United States v. Teletronics Inc., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is needed is not based on a single factor, but rather a conclusion reached by weighing many factors (See Ex parte Forman 230 USPQ 546 (Bd. Pat. App. & Inter. 1986) and In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988).
These factors include the following:
1) Amount of guidance provided by applicant. Applicant has demonstrated within the application how to make compounds and compositions of formula (III). However, the instant specification provides no species of formula (II) wherein the Pep group of L is broader than the subgenuses of claim 8. Examiner notes that the working examples do include species within the scope of Sp as depicted in claim 7.
Furthermore, the examples in the specification are only so broad as to describe a genus wherein L is of the formula Str-Pep-Sp. No working examples exist of any compounds with differing connectivity from that above, or any other substituents or groups as previously mentioned. As was stated in Morton International Inc. v. Cardinal Chemical Co., 28 USPQ2d 1190 “The specification purports to teach, with over fifty examples, the preparation of the claimed compounds with the required connectivity. However...there is no evidence that such compounds exist...the examples of the '881 patent do not produce the postulated compounds...there is...no evidence that such compounds even exist.” The same circumstance appears to be true here. Hence, Applicants must show that these compounds can be made, or limit the claims accordingly.
2) The nature of the invention and predictability in the art. The invention is directed toward cryptophycin derivatives and conjugates thereof. Regarding predictability in the art, chemistry is generally regarded as unpredictable. See In Re Marzocchi and Horton, 169 USPQ at 367 paragraph 3:
“Most non-chemists would probably be horrified if they were to learn how
many attempted syntheses fail, and how inefficient research chemists are.
The ratio of successful to unsuccessful chemical experiments in a normal
research laboratory is far below unity, and synthetic research chemists, in
the same way as most scientists, spend most of their time working out
what went wrong, and why. Despite the many pitfalls lurking in organic
synthesis, most organic chemistry textbooks and research articles do give
the impression that organic reactions just proceed smoothly and that the
total synthesis of complex natural products, for instance, is maybe a labor-
intensive but otherwise undemanding task. In fact, most syntheses of
structurally complex natural products are the result of several years of
hard work by a team of chemists, with almost every step requiring careful
optimization. The final synthesis usually looks quite different from that
originally planned, because of unexpected difficulties encountered in the initially chosen synthetic sequence. Only the seasoned practitioner who
has experienced for himself the many failures and frustrations which the
development (sometimes even the repetition) of a synthesis usually
implies will be able to appraise such work ......Chemists tend not to publish
negative results, because these are, as opposed to positive results, never
definite (and far too copious)...” Dorwald F. A. Side Reactions in Organic
Synthesis, 2005, Wiley: VCH, Weinheim pg. IX of Preface.
The scope of any compounds, compositions, or pharmaceutically acceptable salts where the variables were not those mentioned above are not adequately enabled or defined. Applicants provide to guidance as how the compounds are made.
3) Number of working examples. The compound core depicted with specific substituents as above represents a narrow subgenus for which Applicant has provided sufficient guidance to make and use; however, this disclosure is not sufficient to allow extrapolation of the limited examples to enable the scope of the compounds instantly claimed. Applicant has provided no working examples of any compounds, compositions, or pharmaceutically acceptable salts where the variables were not those mentioned above.
Within the specification, “specific operative embodiments or examples of the invention must be set forth, Examples and description should be of sufficient scope as to justify the scope of the claims, Markush claims must be provided with support in the disclosure for each member of the Markush group. Where the constitution and formula of a chemical compound is stated only as a probability or speculation, the disclosure is not sufficient to support claims identifying the compound by such composition or formula.” See MPEP 608.01(p).
4) Scope of the claims. The scope of the claims is all of the millions of possible compounds represented by general formula (III).
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Given the number of moieties within the scope of L (“a linker group selected from bivalent organic groups having a molecular weight of up to 1000”; “Pep is a… peptidyl moiety”) and Ab (“an oligopeptide or polypeptide”; “an antibody or antibody-like molecule”; “a small organic group having a molecular weight of 750 or lower”; etc.) the claims are incredibly broad.
5) Level of skill in the art. The artisan using Applicant’s invention would be a chemist with a Ph.D. degree and having several years of bench experience.
6) Undue experimentation. 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)."
The conclusion is clearly justified here that Applicant is not enabled for making these compounds or compositions.
Claim 11 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 treating lung or prostate 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." (<http://www.uspto.gov/web/offices/pac/dapp/1pecba.htm#7> ENABLEMENT DECISION TREE, Example F, situation 1). 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 (III). So 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, demonstrated the cytotoxicity of test compounds against KB-3-1 and KB-V1 cells in in vitro experiments (p. 108-109).
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 tumor 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 claims involves the compounds of the following formula (III):
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and their use as potential treatment to cancers, thus, the scope of claims 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.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-4 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Golakoti et al. (J. Am. Chem. Soc.; 1995).
Golakoti et al. discloses Cryptophycin 1 and Cryptophycin 2 isolated from Nostoc sp. GSV 224, a species of cyanobacteria (p. 12030-12031). These compounds have the following structures (p. 12031).
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Golakoti et al. additionally discloses 18 new cryptophycins isolated from Nostoc sp. GSV 224 including the following (p. 12032, Chart 1).
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These compounds are within the scope of formula (I) wherein X is O, R1 is methyl, R2 and R3 are hydrogen, one of R4 and R5 is hydrogen and the other is methyl or hydrogen, one of R7 and R8 is hydrogen and the other is alkyl, R9 is alkoxy or halogen or methyl, and R10 is hydrogen.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-4 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bigot et al. (WO 2017/076998 A1; IDS filed 11/02/2023).
Bigot et al. discloses cryptophycin compounds of formula (I) as below (p. 10).
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The variable “W” is defined as follows (p. 9).
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Bigot et al. does not explicitly disclose a compound wherein R6 is hydrogen, R8 is methylene-N(Me)2, and R10 is hydrogen, -OH, (C1-C4)alkylene-OH, (C1-C4)alkoxy, or (C1-C4)alkyl. However, this limitation is obvious over Bigot et al.
Bigot et al. additionally discloses the following compound (p. 14).
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It would be prima facie obvious for one of ordinary skill in the art to try to substitute the W of the above subgenus, wherein R8 is methylene-N(Me)2, with the methylene-OH group of the compound disclosed by Bigot et al. One would have been motivated to try, with reasonable expectation of success, as Bigot et al. sets forth a closed list of predictable alternatives including (C1-C4)alkyl-OH that can be present in the W position of formula (I). One would therefore be apprised that methylene-OH would yield predictable results.
Conclusion
No claims are allowed.
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/M.E.B./Examiner, Art Unit 1624 02/23/2026
/BRENDA L COLEMAN/Primary Examiner, Art Unit 1624