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 .
Status of the Claims
Claims 1-30 are pending and examined.
Claim of Foreign Priority
Applicant does not claim foreign priority. Applicant’s earliest claimed priority date is January 30, 2017, corresponding to PCT/US17/15608.
Suggestions for Allowance: To overcome the cited prior art, Applicant can limit the subject population to subjects with gliomas and/or brain cancers harboring a H3 K27M mutation.
Claim Rejections - 35 USC § 112 (Prevention)
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 1-30 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for the treatment of specific cancers, e.g., with different degrees of in vitro potency and those conditions known to be represented by such model, are not considered enabled for prevention of all 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. Prevention of cancers is not enabled.
The standard for determining whether the Specification meets the enablement requirement was cast in the Supreme Court decision of Mineral Separation v. Hyde, 242 U.S. 261 (1916) which postured the question: is the experimentation needed to practice the invention undue or unreasonable? As recognized by the court in In re Wands, 858 F.2d 731 (Fed. Cir. 1988), that is still the standard to be applied, determined by consideration of the Wands factors (MPEP 2164.01(A)); namely, nature of the invention, breadth of the claims, guidance of the specification, the existence of working examples, state of the art, predictability of the art and the amount of experimentation necessary. All of the Wands factors have been considered, with the most relevant factors discussed below
Nature of the Invention: As stated in MPEP 2164.05(a), “[t]he initial inquiry” for determining whether the Specification is enabling “is into the nature of the invention, i.e., the subject matter to which the claimed invention pertains.”
In the instant case, the claimed invention pertains to compounds of Formula (10), which are alleged by the Specification to prevent forms of cancer, including brain cancers.
The State of the Prior Art and the Relative Skill of those in the Art: As stated in MPEP 2164.05(a), “[t]he state of the prior art is what one skilled in the art would have known, at the time the application was filed, about the subject matter to which the claimed invention pertains” and, as stated in MPEP 2164.05(b), “[t]he relative skill of those in the art refers to the skill of those in the art in relation to the subject matter to which the claimed invention pertains at the time the application was filed.”
According to the University of Kansas Cancer Center, https://www.kucancercenter.org/outreach/prevention/preventable-cancers#:~:text=No%20cancer%20is%20100%25%20preventable,Breast%20cancer (accessed on March 2, 2026), “No cancer is 100% preventable.” However, risks can be mitigated through diet, physical activity and lifestyle choices.
According to Harvard Health Publishing, https://www.health.harvard.edu/cancer/brain-tumor-overview-a-to-z (accessed on July 31, 2026), “There is no known way to prevent primary brain tumors.”
As discussed above, the instantly claimed invention pertains to compounds of Formula (10), which are alleged by the Specification to treat cancer as a p53 inducer and agonist of Akt/ERK. See Spec., par. 1. At the time the instant application was filed, it would have been known by those of ordinary skill in the art that - compounds, in the vast majority of cases, demonstrate a remarkably high correlation between their structure, specificity and ability to produce a pharmacological effect. At the same time, it would have also been generally assumed that two compounds with similar chemical properties would exhibit similar biological effects. Thus, given a series of compounds that are shown to exert an activity of interest (or given a target of interest), the ordinarily skilled artisan would have expected that a limited genus of related compounds (e.g., compounds exhibiting near equal molecular shapes and volumes, approximately the same distribution of electrons, and similar physical properties such as hydrophobicity, would interact with the given target to elicit a related biological response.
Accordingly, at the time the invention was made, the relative skill of those in the art tasked with identifying compounds exerting an activity of interest would have been high, as the ordinarily skilled artisan would have had, at minimum, a Ph.D. and experience with screening techniques including computer assisted virtual screening techniques such as ligand-based and structure-based design methods. Deciding which technique to use would have been determined by the skilled artisan’s knowledge regarding the compound and target of interest. Ligand based drug design relies on knowledge of a compound or compounds of interest (i.e., ligands) to derive new compounds that will, in theory, similarly interact with the target of interest to elicit the activity of interest. Conversely, structure based drug design relies on knowledge of the three dimensional structure of the target of interest (i.e., receptor, ion channel, or enzyme) to derive new compounds that will, in theory, interact with the target of interest to elicit the activity of interest. In either case, the compounds derived from these techniques (applied alone or in combination) are then subjected to in vitro testing for validation.
The Level of Predictability in the Art: Once a compound has been identified by ligand based and/or structure based drug design methods as potentially binding to the target molecule, it must be evaluated. However, as discussed by Anderson (Chem and Biol 10:787-797, 2003), “it is important to consider that the ranking assigned by the scoring function is not always indicative of a true binding constant, since the model of the target:ligand interaction is inherently an approximation. Usually, several molecules which scored well during the docking run are evaluated in further tests since even the top scoring molecule could fail in vitro assays… Finally, leads are brought into the wet lab for biochemical evaluation” (Page 794, Column 1). By that point, as noted by Thiel (Nature Biotechnol 2:513-519, 2004), “libraries are small and hit rates are on the order of one in ten” (Page 517, Column 2). This low level of predictability is not surprising considering that even minor structural changes can, and frequently will, drastically alter or eradicate a parent compound’s ability to modulate the activity of a specific receptor or enzyme. Indeed, modifying even a single atom in a compound can dramatically change the compound’s overall structure and - even though complementarity in one portion of the compound might be improved by the chemical revision - the overall binding or activity might be severely compromised. This is certainly true in the case. For example, the breadth of compounds of Formula (10) is vast without requiring numerous moieties in each of those compounds shown to be efficacious (i.e., ONC201 and ONC206).
The Amount of Direction Provided by the Inventor / Existence of Working Examples: The amount of direction provided by the Applicant is considered to be determined by the Specification and the working examples. In the instant case, the Specification fails to disclose a any examples of prevention of cancer.
Scope or Breadth of the Claims: As stated in MPEP 2164.01(c), “when a compound or composition claim is not limited by a recited use, any enabled use that would reasonably correlate with the entire scope of that claim is sufficient to preclude a rejection for nonenablement based on how to use” (emphasis added). Thus, as stated in MPEP 2164.08, “[t]he focus of the examination inquiry is whether everything within the scope of the claim is enabled” (emphasis added). Indeed, 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 (Fed. Cir. 1993) (emphasis added).
At the same time, however, it is also recognized that not everything necessary to practice the invention need be disclosed. Nor is it necessary that an Applicant test all the embodiments of his invention. In re Angstadt, 537 F.2d 498 (CCPA 1976) (emphasis added). In fact, as stated by the court in In re Buchner, 929 F.2d 660 (Fed. Cir. 1991), a patent need not teach, and preferably omits, what is well known in the art.
Accordingly, for purposes of enablement, the relevant concern is whether the scope of enablement provided to one skilled in the art by the disclosure is commensurate in scope with the protection sought by the claims. Thus, while “a patent application is entitled to claim his invention generically” it is necessary that “he provide a disclosure sufficient to enable one skilled in the art to carry out the invention commensurate with the scope of his claims". Amgen, Inc., v. Chugai Pharmaceutical Co., Ltd. (Fed. Cir. 1991). As noted by the court in In re Fisher, 427 F.2d 833 (CCPA 1970), the scope of enablement must bear a “reasonable correlation” to the scope of the claims. See also Ak Steel Corp. v. Sollac, 344 F.3d 1234 (Fed. Cir. 2003) and In re Moore, 439 F.2d 1232 (CCPA 1971). As stated in MPEP 2164.08, resolution of this concern requires two stages of inquiry: “[t]he first is to determine how broad the claim is with respect to the disclosure. The entire claim must be considered. The second inquiry is to determine if one skilled in the art is enabled to make and use the entire scope of the claim without undue experimentation”.
As to the first inquiry, as discussed above, the claims are drawn to compounds of Formula (I), which are alleged by the Specification to act as inducers of p53 and agonists of Akt/ERK. The second inquiry is discussed in detail below. With respect to a subject population, there is not a single example of a cancer prevented has been shown.
Amount of Experimentation Necessary: In view of all of the foregoing, at the time the invention was made, it would have required undue experimentation to practice the entire scope of the invention as claimed. As discussed above, the claims are drawn to compounds of Formula (10), which are alleged by the Specification to act as inducers of p53 and agonists of Akt/ERK. Since identifying any compound which is capable of modulating the activity of a specific receptor, ion channel, or enzyme is extremely complex, the nature of the instant invention considered to be one of extreme complexity. Although the relative skill of those in the art to which the invention pertains is high, the state of the art and unpredictability within the art is such that even the most talented artisan (armed with screening techniques including computer assisted virtual screening techniques such as ligand-based and structure-based design methods) could not reasonably predict which of the compounds encompassed by Formula (10) would prevent and type of cancer, if at all. Although the skilled artisan would have known that certain chemical modifications to the disclosed compounds may predictably provide structurally related compounds having similarly activity, the skilled artisan would have also known that even minor structural changes can, and frequently will, drastically alter or eradicate a parent compound’s ability to modulate the activity of a specific receptor or enzyme.
The quantity of experimentation needed
The quantity of experimentation needed is undue experimentation. One of skill in the art would need to definitively determine the specific population of individuals who would need to be treated and would furthermore have to determine which of the claimed compounds would provide for the prevention of brain cancers, among others. To prevent cancer in any patient population, as the instant claims are drawn to, would require undue experimentation to both develop an animal model which would reasonably correlate therewith.
Thus, factors such as "sufficient working examples", "the level of skill in the art" and "predictability", etc. have been demonstrated to be sufficiently lacking in the instantly claimed methods. In view of the breadth of the claim, the chemical nature of the invention, and the lack of working examples regarding the activity of the claimed compounds, one having ordinary skill in the art would have to undergo an undue amount of experimentation to use the invention commensurate in scope with the claims.
The court in Genentech Inc. v. Novo Nordisk A/S (CAFC) 42 USPQ2d 1001, states that, “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion" and "[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable.”
Therefore, in view of the Wands factors and In re Fisher (CCPA 1970) discussed above, to practice the claimed invention herein, a person of skill in the art would have to engage in undue experimentation to test which diseases can be treated or prevented by the compound encompassed in the instant claims, with no assurance of success.
To overcome this rejection, Applicant should narrow the scope of the claims such that they bear a reasonable correlation with the disclosure.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 10-13, 16-23, and 26-30 are rejected under 35 U.S.C. 103 as being unpatentable over Allen et al., (WO2015/073109), in view of Yuen et al., “Histone H3.3 Mutations: A Variant Path to Cancer,” Cancer Cell 24, November 11, 2012, as evidenced by Li et al., “Genome-wide shRNA screen revealed integrated mitogenic signaling between dopamine receptor D2 (DRD2) and epidermal growth factor receptor (EGFR) in glioblastoma,” Oncotarget, Vol. 5, No. 4. March 7, 2014.
Allen teaches using the claimed compound ONC201, as well as Formula (10) compounds generally to treat glioma and other types of brain cancer, CNS tumors, and many others. See par.’s 36, 42, 86, 96, and 105, and prior art claim 8. Prior art claim 8 teaches gliomas as one of only 7 types of tumors. Prior art claim 1 administers compound 1 to said subject. The subject population for treatment includes humans and non-humans, including a cat or dog. See par. 72. Examples compounds include those of Formula (10). Allen teaches treating solid tumors, glioma, brain cancer, medulloblastoma, lymphomas, Ewing’s sarcoma, CNS cancers, neuroblastoma, leukemias, and other cancers. See par. 85-109. A subject is claimed to include those under the age of 65 years. See prior art claim 37.
Li teaches, “all glioblastoma specimens showed a 4-17 fold increase in DRD2 mRNA or a 204 fold enhancement in protein expression.” See Figure 2B and p883, 5th full par. Figure 2 shows overexpression of DRD2 relative to normal tissues. See p885, Figure 2.
Yuen explains that approximately 70%-80% of pediatric gliomas are characterized by histone H3 mutations. However, 5elatively fewer gliomas have K27M substitutions. See p569, 5th full par. Histone H3 mutations have been implicated in a high proportion of malignant pediatric brain cancers. See abstract.
It would have been prima facie obvious to a person having ordinary skill in the art prior to the filing of the instant application to treat gliomas irrespective of the existence or lack thereof of a specific mutation causing the glioma. Additionally, the species of glioma would not appear to form a basis of non-treatment in lieu of the teachings of the cited prior art. This is particularly the case because up to approximately 80% of gliomas are characterized by H3 family mutations and Allen teaches treating gliomas with ONC201 as well as those compounds of Formula (10). As such, there is a reasonable and predictable expectation of success in treating the claimed subject population in view of the teachings that compound 1 can be used to treat glioma, generally.
Claims 10 and 14-20 are rejected under 35 U.S.C. 103 as being unpatentable over Talekar et al., “ONC201 induces cell death in pediatric non-Hodgkin’s lymphoma cells,” Cell Cycle Volume 14, Issue 15, August 1, 2015, in view of Morin et al., (US2013/0102477) (cited in IDS of June 28, 2024), as evidenced by Li et al., “Genome-wide shRNA screen revealed integrated mitogenic signaling between dopamine receptor D2 (DRD2) and epidermal growth factor receptor (EGFR) in glioblastoma,” Oncotarget, Vol. 5, No. 4. March 7, 2014.
Talekar teaches ONC201 will enhance therapeutic responses to treat lymphoma, including pediatric non-Hodgkin’s lymphoma (NHL). ONC201 was shown to increase expression of DR5, which is a pro-apoptotic receptor that is co-induced by ONC201.
Morin teaches H3K27 mutation is a biomarker identifying a subject as having B-cell non-Hodgkin lymphoma. See prior art claims 1-7.
With respect to claims directed to dopamine receptor expression, the examiner notes that these claims do not require a step for detecting or determining expression levels of DRD2 or DRD5, e.g. As such, if a type of cancer taught to be treated always overexpresses DRD2 and underexpresses DRD5, such limitation is met by treatment.
Li teaches, “all glioblastoma specimens showed a 4-17 fold increase in DRD2 mRNA or a 204 fold enhancement in protein expression.” See Figure 2B and p883, 5th full par. Figure 2 shows overexpression of DRD2 relative to normal tissues. See p885, Figure 2.
It would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the instant application to combine the teachings of Talekar and Morin to arrive at a claimed invention. One would be motivated to do so because Talekar teaches ONC201 to treat pediatric NHL and ONC201 increases DR5. Further, H3K27 mutation is a biomarker to identify those subjects with B-cell NHL. As such, if a subject is identified as having B-cell NHL by identifying the H3K27 biomarker, it would be obvious with a reasonable expectation of success to administer ONC201 because it is a known treatment for the same.
Claims 10 and 14-20 are rejected under 35 U.S.C. 103 as being unpatentable over Ishizawa et al., “ONC201 Exerts p53-Independent Cytotoxicity Through TRAIL and DR5 Induction In Mantle Cell Lymphomas,” Blood (2013) 122 (21):3822 (cited in IDS of June 28, 2024), in view of Morin et al., (US2013/0102477), as evidenced by Li et al., “Genome-wide shRNA screen revealed integrated mitogenic signaling between dopamine receptor D2 (DRD2) and epidermal growth factor receptor (EGFR) in glioblastoma,” Oncotarget, Vol. 5, No. 4. March 7, 2014.
Ishizawa teaches ONC201 induces apoptosis is various cancer cell types and acts by upregulating TRAIL-R2/DR5 in solid tumors. ONC201 induced apoptosis in MCL cell lines within 72 hours. MCL is a type of B-cell NHL.
Morin teaches H3K27 mutation is a biomarker identifying a subject as having B-cell non-Hodgkin lymphoma. See prior art claims 1-7.
With respect to claims directed to dopamine receptor expression, the examiner notes that these claims do not require a step for detecting or determining expression levels of DRD2 or DRD5, e.g. As such, if a type of cancer taught to be treated always overexpresses DRD2 and underexpresses DRD5, such limitation is met by treatment.
Li teaches, “all glioblastoma specimens showed a 4-17 fold increase in DRD2 mRNA or a 204 fold enhancement in protein expression.” See Figure 2B and p883, 5th full par. Figure 2 shows overexpression of DRD2 relative to normal tissues. See p885, Figure 2.
It would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the instant application to combine the teachings of Talekar and Morin to arrive at a claimed invention. One would be motivated to do so because Talekar teaches ONC201 to treat pediatric NHL and ONC201 increases DR5. Further, H3K27 mutation is a biomarker to identify those subjects with B-cell NHL. MCL is a type of B-cell NHL. As such, if a subject is identified as having B-cell NHL by identifying the H3K27 biomarker, it would be obvious with a reasonable expectation of success to administer ONC201 because it is a known treatment of the same.
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 §§ 706.02(l)(1) - 706.02(l)(3) 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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-30 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 10,369,154. Although the claims at issue are not identical, they are not patentably distinct from each because the claims of the ‘154 patent are directed towards treating a species of glioma, which is a midline glioma, in cancers with a histone H3 K27M mutation by administering ONC201 (i.e., the claimed compound). The instant claims are directed towards treating all gliomas, which includes midline gliomas as evidenced by dependent claim 2, which includes midline gliomas as a subspecies of cancer to be treated by the claimed methods.
Claims 1-30 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 10,172,862. Although the claims at issue are not identical, they are not patentably distinct from each because the claims of the ‘862 patent are directed towards treating a species of glioma, which is a midline glioma, in cancers with a histone H3 K27M mutation by administering ONC201 (i.e., the claimed compound). The instant claims are directed towards treating all gliomas, which includes midline gliomas as evidenced by dependent claim 2, which includes midline gliomas as a subspecies of cancer to be treated by the claimed methods.
Claims 10-30 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-28 of U.S. Patent No. 10,946,022. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘022 patent are directed towards treating gliomas with the claimed H3K27M mutations, including pets, pediatrics, and others. In particular, the claims of the ‘022 patent are directed to using ONC206, which is a compound that falls within Formula (10) as claimed in instant claim 10. The subject population and claimed genetic profile are the same.
Claims 1-30 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 12,102,639. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘639 patent are directed towards treating brain cancers, including gliomas, with the claimed H3K27M mutations, including pets, pediatrics, and others. The main distinction in the ‘639 patent is that it refers to brain cancers more generally that harbor a H3K27M mutation in independent claim 1.
Claims 10, 11, and 14-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent No. 11,116,771. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘771 patent are directed to treating cancers including neuroendocrine cancers with ONC201. Dependent claims 3 and 4 require such cancer to have a H3 and HSK27M mutation. These cancers fall within the scope of instant claims 10 and 11 as claim 10 is directed to treating neuroendocrine tumors. Claim 14 depends from claim 10 and requires the neuroendocrine tumor to have a H3.3 or H3.1 K27M mutation.
As such, no claim is allowed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JARED D BARSKY whose telephone number is (571)272-2795. The examiner can normally be reached on 9-5 M-F.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy Clark can be reached on 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JARED BARSKY/Primary Examiner, Art Unit 1628
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