DETAILED ACTION
Claims 1-16 are currently pending in the instant application. Claims 1-15 are rejected. Claim 16 is withdrawn from consideration as being for non-elected subject matter.
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 .
Election/Restrictions
Applicant’s election without traverse of Group I and the species compound 43:
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in the reply filed on 1 March 2026 is acknowledged.
According to MPEP 803.02, the examiner has determined whether the elected species is allowable. Applicants’ elected species appears allowable. Therefore, the search and examination has been extended to the entirety of Group I. Claims 14 and 15 have been amended from compound claims to method of treatment claims and have been examined in their entirety along with product claims 1-13.
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 1-6 and 11-15 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13, 15, and 16 of copending Application No. 18/554,474 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the conflicting claims are drawn to products of the formula (IV):
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(conflicting claim 1) wherein v can be 0 (conflicting claim 6); Y can be H or F (conflicting claim 1) and H (conflicting claims 15 and 16); X can be N (conflicting claims 15 and 16); W1 is C(O) (conflicting claim 1); n is 1 or 2 (conflicting claim 1 and 8); U is NH (conflicting claim 7); W2 is C(O) (conflicting claim 1); L2 is
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(conflicting claim 1 and 8); R1 is H (conflicting claim 2); R2 is H (conflicting claim 3); and R4 is H (conflicting claim 1). The conflicting claims correspond to the instant formula (IV) for example wherein formula (IV):
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has Y as F or H; v is 0 or 1; X is N; L is a linker moiety which can be:
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more particularly to formula (III):
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. Conflicting method claims 9-11 correspond to applicants’ instant method claims of treating a disease caused by an activating mutation of the PI3KCA gene, or a tumor disease, neurological disease, or immunological disease.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim Rejections - 35 USC § 112
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 1-15 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 compounds of the formula (IV) or a prodrug, tautomer, solvate, or pharmaceutically acceptable salt thereof, does not reasonably provide enablement for a metabolite thereof. 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 or use the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is undue. These factors include, but are not limited to: (a) breadth of the claims; (b) nature of the invention; (c) state of the prior art; (d) level of one of ordinary skill in the art; (e) level of predictability in the art; (f) amount of direction provided by the inventor; (g) existence of working examples; and (h) quantity of experimentation needed to make or use the invention based on the content of the disclosure. (See Ex parte Forman 230 USPQ 546 (Bd. Pat. App. & Inter. 1986) and In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988).
The above factors, regarding the present invention, are summarized as follows:
(a) Breadth of the claims - The breadth of the claims is products of the formula (IV) or a prodrug, tautomer, solvate, or pharmaceutically acceptable salt thereof and methods of treatment as well as presently unknown compounds embraced by the term metabolite and methods of treatment.
(b) Nature of the invention - The nature of the invention is products of the formula (IV) or a prodrug, metabolite, tautomer, solvate, or pharmaceutically acceptable salt thereof and methods of treatment as well as presently unknown compounds embraced by the term metabolite and methods of treatment.
(c) State of the prior art –The prior art recognizes metabolites as intermediates and products of biotransformations or metabolism. Fura, A. (DDT, 2006, 11, page 133, internal citations omitted) teaches the various types of small molecules that can be encompassed by this term: Biotransformation reactions can be accompanied by various events, such as the formation of chemically stable metabolites, which are devoid of pharmacological or toxicological activities, or the generation of short-lived
chemically-reactive metabolites, which can lead to toxicological activation. Biotransformation reactions can also result in the formation of chemically stable metabolites with pharmacological activity (on or off target). Accordingly, metabolites can include compounds which are rendered (in vivo) biologically inactive, toxic, biologically active with a different target than the parent compound or more/less active than the parent compound with the same target.
(d) Level of one of ordinary skill in the art - The artisans synthesizing Applicant’s compounds to use in the treatment would be a collaborative team of synthetic chemists and/or health practitioners, possessing commensurate degree level (at least a B.S. degree) and/or skill in the art, as well as several years of professional experience.
(e) Level of predictability in the art – Anari et al. (DDT, 2005, 10, pages 714-715, internal citations omitted) have addressed the situations in which metabolite predictability may be available. First, Anari et al. suggest that:
An experienced scientist familiar with various in vivo biotransformation pathways should be able to predict the potential metabolites of a given substrate based on the various functional groups present in that molecule.
Any measure of predictability that would result from the situation above is dependent on the artisan synthesizing Applicant's metabolites being well above that of ordinary skill in the art. A person having ordinary skill in the art would not have sufficient knowledge of the metabolic pathways involved with Applicant’s instant invention such that a meaningful prediction of metabolites could be made. Second, Anari et al. suggest that software packages can be used to predict metabolite formation, in that:
[T]he metabolic pathways of a given substrate can be predicted based on knowledge of the metabolism of similar structures in the database.
Any measure of predictability that would result from the situation above is dependent on the existence of a significant pool of data on the metabolism of structurally related compounds for which Applicant has not provided. Third, Anari et al. teach the use of empirically based expert software that can be used to predict metabolites based on expert rules of metabolism. While the third method appears to be useful for the prediction of metabolites, Anari et al. concede that the expert software often fails to predict metabolites that result from extensive metabolism:
[U]nexpected metabolites are observed occasionally whose molecular masses have not been anticipated. These metabolites often are formed by extensive metabolism of the parent drug via multiple enzymatic reactions in addition to non-enzymatic rearrangements.
Furthermore, and more importantly to the statute at issue is whether any predictability of the structure of a metabolite, which would enable a person having ordinary skill in the art to make the invention, corresponds to a predictability in the biological role of the metabolite, which would enable a person having ordinary skill in the art to use the invention. There is a significant lack of predictability in the art in determining whether a given compound will possess biological activity and, if so, how the biological activity relates to given a molecular pathway or disease state.
(f) Amount of direction provided by the inventor - The application does not provide direction with respect to making and using metabolites with a text search only provided two instances of the word “metabolite” in the specification. Furthermore, Applicant has not provided any guidance that would lead a person of ordinary skill in the art to be able to predict certain metabolites or predict the activity of these metabolites.
(g) Existence of working examples - While the claims recite metabolites, no working examples show their formation. The specification shows no evidence of the identification and actual existence of any metabolite. Hence, Applicant must demonstrate the identification of metabolites or limit the claims accordingly.
(h) Quantity of experimentation needed to make or use the invention based on the content of the disclosure – Given the state of the art and lack of predictability discussed in section (e), undue experimentation is needed to practice the full scope of Applicant’s instant invention especially in view of the lack of direction discussed in sections (f) and (g). Nedderman, A. N. R. (Biopharm. Drug Dispos. 2009, 30, pages 153-154, internal citations omitted) teaches that multiple studies and methods are needed to characterize metabolites, in that:
[M]etabolite identification studies have typically been initiated during the compound selection phase of drug discovery with in vitro investigations using microsomes, hepatocytes or alternative metabolising systems and the analysis of in vivo samples from relevant animal species. Following these studies, the synthesis and pharmacological testing of potentially active metabolites would often be considered where appropriate. In addition to these structural elucidation studies, an in vitro experiment (most commonly a glutathione conjugation assay) to assess the propensity of the compound to undergo metabolism involving reactive pathways would typically be conducted in early discovery so that elimination of the reactive pathway via chemical re-design can be attempted. During drug development, definitive metabolite identification studies are performed in humans and all safety species using radiolabelled material.
Nedderman continues by stating that these studies require such a large amount of resources that they are often postposted, in that:
[T]he majority of metabolite identification work has historically been conducted late in drug discovery and late in drug development, primarily due to the complexity of structural elucidation and the associated time and resource requirements.
Accordingly, the studies necessary to perform a full characterization of a given compound’s metabolites are complicated and require experimentation that would be considered undue on a person having ordinary skill in the art given the lack of guidance provided by Applicant.
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 determination that undue experimentation would have been needed to make and use the claimed invention is not a single, simple factual determination. Rather, it is a conclusion reached by weighing all the above noted factual considerations. (In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404). These factual considerations are discussed comprehensively in MPEP § 2164.08 (scope or breadth of the claims), § 2164.05(a) (nature of the invention and state of the prior art), § 2164.05(b) (level of one of ordinary skill), § 2164.03 (level of predictability in the art and amount of direction provided by the inventor), § 2164.02 (the existence of working examples) and § 2164.06 (quantity of experimentation needed to make or use the invention based on the content of the disclosure).
Based on a preponderance of the evidence presented herein, the conclusion that applicant is insufficiently enabled for making and using metabolites is clearly justified along with the conclusion that applicant is only enabled for treating with the formula (IV) or a prodrug, tautomer, solvate, or pharmaceutically acceptable salt thereof.
Claim 15 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 the treatment of a tumor disease, overgrowth syndrome, neurological disease, or immunological disease modulated by PI3Ks (see page 18 of the instant specification) does not reasonably provide enablement for the treatment of any tumor disease, overgrowth syndrome, neurological disease, or immunological disease. 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 in scope with the claim language. 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). See MPEP § 2164.08. That some experimentation may be required is not fatal; the issue is whether the amount of experimentation required is “undue.” In re Vaeck, 947 F.2d 488, 495, 20 USPQ2d 1438, 1444 (Fed. Cir. 1991).
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is undue. These factors include, but are not limited to: (a) breadth of the claims; (b) nature of the invention; (c) state of the prior art; (d) level of one of ordinary skill in the art; (e) level of predictability in the art; (f) amount of direction provided by the inventor; (g) existence of working examples; and (h) quantity of experimentation needed to make or use the invention based on the content of the disclosure. Ex parte Forman 230 USPQ 546 (Bd. Pat. App. & Inter. 1986) and In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988).
The above factors, regarding the present invention, are summarized as follows:
Breadth of the Claim – Claim 15 is drawn to a method of treatment of a tumor disease, overgrowth syndrome, neurological disease, or immunological disease (please note the typo “aimmunological disease” last line of the claim). The claims Accordingly, the claims are drawn to treating a broad scope of diseases and disorders and cancers.
Nature of the Invention – The nature of the invention pertains to a method of modulating PI3K kinase activity (see page 1 of the specification), specifically PI3K inhibitory activity, page 2 of the specification.
State of the Prior Art and Predictability in the Art – Even in view of the seemingly high level of skill in the art, there is no absolute predictability when determining the physiological effects of a compound of formula (IV) against any and all tumor disease and any and all diseases overgrowth syndrome, neurological disease, or immunological disease. 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. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). Lipinski et al. (Trends in Cancer, 2016, 49-63) even teach “[g]enomic aberrations differ between cancers of the same histological type, to the extent that no two tumors are thought to show an identical somatic genetic aberration profile.” See e.g., page 49. Therefore, a skilled artisan would reasonably expect the efficacy of treatment methods to vary when considering the diverse causes and symptoms associated with any and all tumor growths.
Relative Skill of Those in the Art – The artisan making and using applicant’s pharmaceutical compound would be a synthetic chemist and/or a health practitioner, possessing a commensurate degree level and/or skill in the art, as well as several years of professional experience. The level of skill in the art is high; however, due to the unpredictability in the pharmaceutical art and the wide scope of cancers, it is difficult to assess the potential pharmacological activity of a compound of formula (IV) against any and all tumor growths, overgrowth syndromes, neurological diseases or immunological diseases..
Amount of Direction/Guidance Provided and Existence/Absence of Working Examples – The specification provides a list of cancers and diseases on pages 16-17. Pages 63-67 provides in vitro data. However, the disclosure does not provide support for treating any and all tumor disease, overgrowth syndrome, neurological disease, or immunological disease. There is no actual evidence of the effectiveness in treating the full scope claimed. Ex parte Stevens, 16 USPQ2d 1379.Quantity of Experimentation Necessary – The quantity of experimentation needed to use the invention based on the content of the disclosure is undue. One of skill in the art would need to determine which specific cancer or disease or disorder not embraced by the instant disclosures relation to modulating PI3K kinase activity would benefit from the pharmacological activities of a compound of formula (IV) by administering said compound to a subject. Using the full scope of the instant claim is made further burdensome when one considers that even human testing “limited to one compound and two types of cancer” was not “commensurate with the broad scope of utility asserted and claimed.” In re Buting, 57 CCPA 777, 418 F.2d 540, 163 USPQ 689. The claimed invention would require a person having ordinary skill to invest an indefinite amount of experimentation clearly beyond what can be considered as routine.
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 test of enablement is not whether any experimentation is necessary, but whether, if experimentation is necessary, it is undue. In re Angstadt, 537 F.2d 498, 504, 190 USPQ 214, 219 (CCPA 1976). In view of the Wands factors and In re Fisher (CCPA 1970) discussed above, a person of skill in the art would have to engage in undue experimentation to test which tumor disease, overgrowth syndrome, neurological disease, or immunological disease can be treated by a compound of formula (IV), with no assurance of success.
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 1-15 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.
Regarding claims 1, 4, 5, 7, 10, 11, 14, and 15 forms of the phrases "particularly," “more particularly,” “in particular”, and “even more particularly” found in multiple instances in the claims renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. For example, in instant claim 1, is v 0-4, or is v limited to 0-2, or is v limited to only 0 or 1. See MPEP § 2173.05(d).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to REBECCA L ANDERSON whose telephone number is (571)272-0696. The examiner can normally be reached Monday-Friday from 6am-2pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Andrew Kosar can be reached at 571-272-0913. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/REBECCA L ANDERSON/Primary Examiner, Art Unit 1626 ____________________ 9 June 2026
Rebecca Anderson
Primary Examiner
Art Unit 1626, Group 1620
Technology Center 1600
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