DETAILED ACTION
STATUS OF THE APPLICATION
Receipt is acknowledged of Applicants’ Amendments and Remarks, filed 8 February 2024, in the matter of Application No. 18/436,626. Said documents have been entered on the record. The Examiner further acknowledges the following:
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-20 are pending.
No claims have been amended.
No claims have been cancelled.
Thus, claims 1-20 represent all claims currently under consideration.
Priority
The Examiner acknowledges U.S. Provisional Application No. 63/213,871, filed on 23 June 2021.
Domestic Priority data as claimed by Applicant:
This application is a CON of 17/847,935 (06/23/2022)
17/847,935 has PRO 63/213,871 (06/23/2021)
Information Disclosure Statement (IDS)
The information disclosure statement (IDS) submitted on 23 May 2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS is being considered by the Examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the Examiner on form PTO-892, they have not been considered.
Specification
The disclosure is objected to because of the following informalities:
In paragraph [0031], the word “comprising” should be deleted and replaced by the word “of”.
Appropriate correction is required.
Claim Objections
Claim 1 is objected to because of the following informalities:
In lines 4-5, “…C1-C6 unsubstituted or substituted, alkyl,…” should read “…C1-C6 unsubstituted or substituted alkyl,…”
In line 6, “…PO3H, , CONH2…” should read “…PO3H, CONH2…”
In line 6, “…CONHOH, and SO2NHR…” should read “…CONHOH, or SO2NHR…”
In line 7, “…benzamidazolyl…” should read “…benzimidazolyl…
Claim 2 is objected to because of the following informalities:
In line 6, “…CONHOH, and SO2NHR…” should read “…CONHOH, or SO2NHR…”
In line 7, “…benzamidazolyl…” should read “…benzimidazolyl…
Claim 8 is objected to because of the following informalities:
In line 3, “…a pharmaceutical composition…” should read “…the pharmaceutical composition …”
Appropriate correction is required.
Claim Interpretation
The term “isomer” as recited in instant claims 1-4 will be interpreted in a manner consistent with the written description (Specification; paragraph [0011]) as encompassing stereoisomers of a compound including, or consisting of, structural formula (I) and/or (II).
The term “treatment” as recited in instant claims 8-20 will be interpreted in a manner consistent with the written description (Specification; paragraph [001100]) as referring to treatment of a cancer in a subject and includes preventing, inhibiting or ameliorating the cancer in the subject.
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 1-20 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 the phrase “…where R4 is H, C1-C6 unsubstituted or substituted, alkyl, cycloalkyl, cycloalkyl, aryl, phenyl, heteroalkyl, heterocycloalkyl, or heteroaryl…” yet as written, the scope C1-C6 of does not clearly apply to all of the subsequent organic functional group designations. This ambiguity is not sufficiently addressed in the written description and therefore renders the instant claim indefinite. For example: (1) a cycloalkyl group cannot be a C1 or C2 group (i.e., must be C3 or greater); (2) an aryl group cannot be a C1-C5 group (i.e., must be C6); (3) a phenyl group cannot be a C1-C5 group (i.e., must be C6); (4) a heterocycloalkyl group cannot be a C1 group (i.e., must be C2 or greater); and (5) a heteroaryl group cannot be a C1-C3 group (i.e., must be C4 or greater). Alternatively, in the event that the term “C1-C6” is meant to limit only the substituents of the subsequent organic functional group designations, then the phrase “…where R4 is H, C1-C6 unsubstituted or substituted, alkyl,…” should read “…where R4 is H, unsubstituted or C1-C6 substituted alkyl,…” Further clarification is required. The Examiner notes that adequately addressing this ambiguity would ameliorate this claim rejection.
Regarding claims 2-20, these dependent claims do not resolve the indefiniteness of claim 1 described above.
Claim Rejections - 35 USC § 112(a) – Scope of Enablement
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 8-20 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 treating the recited cancers, does not reasonably provide enablement for preventing the recited cancers. 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.
Enablement is considered in view of the Wands factors (MPEP § 2164.01(a)). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue,’ not 'experimentation.'" (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (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 or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case are discussed below.
The nature of the invention
Claim 8 encompasses a method of treatment of a subject having, or suspected of having, cancer, comprising administering an effective amount of the pharmaceutical composition according to claim 6 to the subject. The term “treatment” as recited in instant claims 8-20 will be interpreted in a manner consistent with the written description (Specification; paragraph [001100]) as referring to treatment of a cancer in a subject and includes preventing, inhibiting or ameliorating the cancer in the subject. Thus, claim 8 and dependent claims 9-20 encompass a method for preventing cancer.
Claims 9-10 encompass the method of treatment of claim 8, wherein the administering comprises systemic or local administration, respectively.
Claims 11-13 encompass the method of treatment of claim 8, further comprising assaying one or more of: CXCR4, TNF, IL-1beta, IL-6, and IL-8 in a subject sample obtained from the subject prior to or after administering the effective amount of the pharmaceutical composition, respectively.
Claims 14-17 encompass the method of treatment of claim 8, further comprising administering an additional therapeutic agent to the subject; wherein the additional therapeutic agent comprises an additional inhibitor of a proinflammatory cytokine or chemokine, a nucleic acid inhibitor, an antibody, an antigen-binding antibody fragment, an aptamer, an inorganic or organic small molecule inhibitor, or a combination of any two or more thereof; and wherein the additional therapeutic agent comprises an anti-cancer agent.
Claims 18-19 encompass the method of treatment of claim 8, further comprising an adjunct anti-cancer treatment to the subject, wherein the adjunct anti-cancer therapy comprises surgery and/or radiation treatment.
Claim 20 encompasses the method of treatment of claim 8, wherein the cancer is prostate cancer or castration resistant prostate cancer.
The breadth of the claims
The claims are broad in that they encompass the prevention of the recited cancers, as well as a broad range of additional therapeutic agents.
The specification does not define “preventing”. In absence of a limiting definition by the applicants, “preventing” is interpreted as defined according to IIME as provided in Wojtczak, A. (2002) Glossary of Medical Education Terms Medical Teacher 24(4): 357; 1-25. IIME defines “prevention” as promoting health, preserving health, and to restore health when it is impaired, and to minimize suffering and distress (page 16, “Prevention”). IIME states that “primary prevention refers to the protection of health by personal and community wide effects, such as preserving good nutritional status, physical fitness, and emotional well-being, immunizing against infectious diseases, and making the environment safe.” IIME states that “secondary prevention can be defined as the measures available to individuals and populations for the early detection and prompt and effective intervention to correct departures from good health”. IIME further states that tertiary prevention consists of the measures available to reduce or eliminate long-term impairments and disabilities, minimize suffering caused by existing departures from good health”.
Thus, in its broadest reasonable interpretation, preventing the recited cancers indicates that that the onset of the cancer never occurs and the patient’s health is protected and preserved.
The amount or direction provided by the inventor / the existence of working examples
The examples disclose a synthetic scheme for a compound having structural formula (II) (Specification; paragraphs [00164]-[00173]; Figure 2).
The examples do not demonstrate prevention of the cancers recited in the instant claims. The disclosure also does not identify, or demonstrate through working examples, a method that can be used by one of ordinary skill in the art to predictably determine that a subject would develop one of the claimed cancers in order to establish that cancer was prevented using the claimed method.
The state of the prior art / the level of predictability in the art
There are no art recognized methods that can be used to predictably determine that cancer onset was prevented using the claimed method or to identify patients who would predictably develop cancer in order to identify that prevention was achieved using therapeutic approaches. Rather, the state of the art indicates that cancer development was not predictable.
Lewandowska, A.M., et al (2017) Environmental risk factors for cancer – review paper Ann. Agric. Environ. Med. 26(1); 1-7 teaches that the cancerous process is a result of disturbed cell function. This is due to the accumulation of many genetic and epigenetic changes within the cell, expressed in the accumulation of chromosomal or molecular aberrations, which leads to genetic instability. It is difficult to assess the validity of individual etiological factors, but it can be concluded that interaction of various risk factors has the largest contribution for the development of cancer. Environmental, exogenous and endogenous factors, as well as individual factors, including genetic predisposition, contribute to the development of cancer (page 1, right column, paragraph 1). Lewandowska discusses numerous factors that contribute to the development of cancer including physical factors such as exposure to electromagnetic fields, ionizing radiation, and ultraviolet radiation (pages 2-3); chemical factors including tobacco smoking, alcohol, and other chemicals (pages 3-4); and biological factors including diet, physical activity, mutagenic and carcinogenic compounds in food, nitrosoamines, and infections (pages 4-5). Lewandowska teaches that, additionally, some epidemiological research suggests that the influence of environmental factors will further affect the cell’s genetic material. This is connected with the spreading of carcinogens in various geographical zones. While some are well known and can be modified, there are certain factors that cannot be fully controlled, such as industrialization (page 6, left column, paragraph 2).
The teachings of Lewandowska demonstrate that, while it was known that cancer is caused by disturbed cell function, numerous factors have been identified that could lead to such disfunction and cell disfunction is likely caused by the interaction of various risk factors. Lewandowska also teaches factors such as genetic predisposition and environmental factors that can contribute to the formation of cancer but are beyond the control of an individual subject. These teachings demonstrate that there was no specific known cause of cancer and, therefore, suggest that there would be no method to predictably determine that cancer would have developed in order to establish that it was prevented.
Cuzick, J. (2017) Preventive therapy for cancer Lancet Oncol 18; e472- e482 teaches the use of therapeutic preventative measures in addition to weight control and physical activity, such as low-dose aspirin for adults without the risk of hypertension or gastrointestinal bleeding, universal HPV vaccination, and other therapies such as anti-oestrogen drugs for breast cancer prevention targeting high-risks groups to “maintain a favorable benefit-risk ratio” (abstract). While Cuzick is identifying therapeutic regimens to prevent cancer, Cuzick also teaches “the balance of risks and benefits is inherently more challenging for preventative than for therapeutic interventions. Only a small fraction of the apparently healthy people who receive a preventative treatment would ultimately develop the specific type of cancer being targeted. Moreover, the absence of the cancer is not quantifiable at an individual level, whereas all those treated will incur a risk of side-effects which are identifiable on an individual basis” (page e472, left column, paragraph 2).
Cuzick demonstrates that the prevention of cancer is not predictable and that numerous factors contribute to the development of cancer. Additionally, Cuzick teaches difficulties in preventing cancer with therapeutic methods and specifically states that the absence of cancer is not quantifiable on an individual level, a statement which demonstrates that the determination of whether or not cancer was prevented is unpredictable.
DeCensi, A., et al (2015) Barriers to preventative therapy for breast and other major cancers and strategies to improve uptake ecancer 9(595); 1-12 teaches that the global cancer burden continues to rise but the utilization of preventative therapy has been poor due to various barriers. DeCensi teaches barriers such as the lack of physician and patient awareness, fear of side effects, and licensing and indemnity issues. DeCensi provides a review discussing the barriers and proposes strategies to overcome them including improving awareness and countering prejudices by highlighting the important differences between preventative therapy and cancer treatment. DeCensi further teaches that future research to improve therapeutic cancer prevention needs to include improvements in the prediction of benefits and harms and improvements in safety profiles of existing agents by experimentation with dose (abstract). DeCensi teaches that for preventative therapy, we cannot identify individuals whose cancer was prevented or risk was substantially reduced because of the lack of measurable biomarkers of efficacy that currently exist for other diseases such as cardiovascular diseases, prevention of diabetes complications or osteoporotic bone fractures. Therefore, from that person’s point of view, they either took medication unnecessarily or, in the worst-case scenario, unnecessarily suffered the adverse effects of such therapy (page 2, paragraph 1).
The teachings of DeCensi demonstrate that, while preventative therapies could be beneficial if various barriers are overcome, there was no method known that could be used to identify individuals whose cancer was prevented because of the lack of measurable biomarkers.
The teachings of Lewandowska, Cuzick, and DeCensi demonstrate that there was no art recognized method of determining whether a patient would predictably develop cancer and, therefore, there is no predictable way to determine that cancer was prevented using the claimed method.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
As discussed above, there is no disclosed or art recognized method through which an ordinarily skilled artisan would be able to determine that a subject would have predictably developed one of the claimed cancers in order to apply the claimed treatment as a preventative measure. Furthermore, there is no known or disclosed method that could be used to establish that cancer was prevented as there is no predictable way to know that the subject being treated would have developed a cancer without the treatment. As such, in order to implement the invention as claimed, one of ordinary skill in the art would have to participate in undue experimentation to identify a method that could be used to establish that cancer was prevented, with the possibility that no such method could be found.
In view of the Wands factors discussed above, a person of ordinary skill in the art would have to engage in undue experimentation to practice the full scope of the claimed invention. As such, the instant claims were determined to not meet the scope of enablement requirement of 35 USC 112(a).
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 1-4 and 6-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 and 5-20 of U.S. Patent No. 11,931,360 B2.
Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding instant claims 1-2, claims 1-2 of U.S. Patent No. 11,931,360 B2 recites structural formula (I) that comprises an identical chemical formula to the instantly claimed structural formula (I).
Regarding instant claims 3-4, claim 3 of U.S. Patent No. 11,931,360 B2 recites structural formula (II) that discloses a species with an identical chemical formula to the instantly claimed structural formula (II) and is an isomer of structural formula (I). See MPEP § 2144.09.
Regarding instant claims 6-20, claim 5-20 of U.S. Patent No. 11,931,360 B2 teaches every limitation of the instant claims.
Claim 5 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 of U.S. Patent No. 11,931,360 B2 in view of Rautio et al. (Nat. Rev. Drug. Disc. 2008, 7, 255-270; hereinafter “Rautio”).
Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding claim 5, claim 1 of U.S. Patent No. 11,931,360 B2 recites structural formula (I) that comprises an identical chemical formula to the instantly claimed structural formula (I) of claim 1 on which the instant claim depends.
Claim 1 of U.S. Patent No. 11,931,360 B2 fails to teach the compound of claim 1, wherein the compound is an ester, amide, or hydrate of structural formula (I), as recited in instant claim 5.
This deficiency is remedied by Rautio, who teaches the following.
Rautio teaches the design and clinical applications of prodrugs, wherein prodrugs are bioreversible derivatives of drug molecules that undergo an enzymatic and/or chemical transformation in vivo to release the active parent drug (Rautio; Title; Abstract). Rautio further teaches that prodrugs have become an established tool for improving physicochemical, biopharmaceutical, or pharmacokinetic properties of pharmacologically active agents (Rautio; Abstract). Of particular note, Rautio teaches that esters are the most common prodrugs used, most often to enhance the lipophilicity and thus the passive membrane permeability of water-soluble drugs by masking charged groups (Rautio; page 256; Col. 2, paragraph 3; page 257, Table 1). In addition, Rautio teaches that amides are used as prodrugs of carboxylic acids and amines, and are often designed for enhanced oral absorption and are usually hydrolyzed enzymatically (Rautio; page 259, Col. 2, paragraph 2).
The prior art as taught by U.S. Patent No. 11,931,360 B2 and Rautio reside in the overlapping technical area of ester and amide derivatives of small molecule compounds of pharmacological interest, and are therefore deemed analogous art as described in MPEP § 2141.01(a). As such, the skilled artisan would be sufficiently motivated to incorporate the teachings of Rautio into the compound of structural formula (I) of claim 1 of U.S. Patent No. 11,931,360 B2 to pursue a prodrug compound with improved pharmacokinetic properties with a reasonable expectation of success. Such an endeavor would result in combining prior art elements according to known methods to yield predictable results, as described in MPEP § 2143(I)(A), and would also result in applying a known technique to a known device (method, or product) ready for improvement to yield predictable results, as described in MPEP § 2143(I)(D).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified U.S. Patent No. 11,931,360 B2 to incorporate the teachings of Rautio to arrive at the compound of claim 1, wherein the compound is an ester or an amide of structural formula (I). The motivation to do so would permit the skilled artisan to pursue, with a reasonable expectation of success, a prodrug compound with enhanced lipophilicity, passive membrane permeability, and enhanced oral absorption, as described above.
Conclusion
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/D.R./Examiner, Art Unit 1692
/AMY C BONAPARTE/Primary Examiner, Art Unit 1692