DETAILED ACTION
This action is in response to papers filed on 10/20/2025. Claims 1-15,18-24, 28-32, 36, 38, 43, and 48-49 of Abrahmsén et al., 17760644 (03/15/2022) are pending examination on the merits: claims 16-17, 25-27, 33-35, 37, 39-42, 44-47 and 50-54 are canceled, claims 1-6, 8-15, 24, 30, 36, 38, 43, and 48 are amended, and claims 10-14, and 19-23 are withdrawn. Claims 1-9, 15, 18, 24, 28-32, 36, 38, 43, and 48-49 are rejected.
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
This application is a 371 of PCT/EP2020/076126 (09/18/2020), which claims benefit of 63/028,477 (05/21/2020), and claims benefit of 62/993,509 (03/23/2020) and claims benefit of 62/902,214 (09/18/2019).
Information Disclosure Statement
The Information Disclosure Statements (IDS) submitted on 10/10/2022 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner
Election/Restriction
REQUIREMENT FOR UNITY OF INVENTION
In a response filed on 10/20/2025, Applicant elected a single species of the different compounds that reactivate the mutant p53 (c.f., claim 8), to which the claims shall be restricted if no generic claim is finally held to be allowable.:
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Applicant’s Remarks at page 10.
As detailed in the following rejections, the generic claim encompassing the elected species was not found patentable. Therefore, the provisional election of species is given effect, the examination is restricted to the elected species only, and claims not reading on the elected species are held withdrawn. MPEP 803.02; Ex parte Ohsaka, 2 USPQ2d 1460, 1461 (Bd. Pat. App. lnt. 1987). Accordingly, claims 10-14, and 19-23 are withdrawn.
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 1-9, 15, 24, 30-32, 36, 38, 43, 48, and 49 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 treatment of myeloid malignancies using a combination therapy of a P53 inhibitor and a Bcl-2 inhibitor per Examples 1 and 2 on pages 82 and 89 respectively, does not reasonably provide enablement for the treatment of all hyperproliferative malignancies in a subject, especially when compared to claim 5 which includes treatment with the compound that reactivates the p53 mutant, a metabolite thereof, or a degradation product thereof. This includes many structurally different compounds and many different hyperproliferative malignancies for example.
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.
Particularly relevant to the instant case is the issue as to whether the specification provides embodiments allowing use of the claimed invention without requiring undue experimentation by one of ordinary skill in view of the highly unpredictable nature of affecting enzymes, and treatment of various hyperproliferative diseases such as rare cancers, where there is no proven cure the disease.
“[An inventor] must not be permitted to achieve . . . dominance by claims which are insufficiently supported and hence not in compliance with the first paragraph of 35 U.S.C. 112. That paragraph requires that the scope of the claims must bear a reasonable correlation to the scope of enablement provided by the specification to persons of ordinary skill in the art. In cases involving predictable factors, such as mechanical or electrical elements, a single embodiment provides broad enablement in the sense that, once imagined, other embodiments can be made without difficulty and their performance characteristics predicted by resort to known scientific laws. In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved.” In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
Accordingly, the critical element here is how broad the claims are compared to the level of unpredictability in the art.
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 more 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).
[In re Sichert, 196 USPQ 209 (CCPA 1977)]
To be enabling, the specification of the patent 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 (Fed. Cir. 1993). Explaining what is meant by “undue experimentation,” the Federal Circuit has stated:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which the experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996).
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
1) the quantity of experimentation necessary,
2) the amount of direction or guidance provided,
3) the presence or absence of working examples,
4) the nature of the invention,
5) the state of the prior art,
6) the relative skill of those in the art,
7) the predictability of the art, and
8) the breadth of the claims.
The nature of the invention & breadth of the claims: The claims are directed to a method of treating hyperproliferative malignancy in a subject comprising administering to the subject a therapeutically effective amount of a compound that reactivates a mutant p53, and an inhibitor of an antiapoptotic Bcl-2 family protein. The claims are broad insofar as claim 1, for example, is directed to the treatment of all hyperproliferative malignancy in a subject using a therapeutically effective amount of any compound that reactivates p53 (c.f., Applicant provides a laundry list of compounds in claim 8 and narrows this in claim 9), and any inhibitor of Bcl-2 family protein, both known and those yet to be discovered, without being reasonably enabling. Moreover, expressions like "a compound that can give reactivation of a mutant p53" and "an inhibitor of an antiapoptotic Bcl-2 family protein" are functional definitions that do not define the compound used in terms of a technical feature such as a structure or sequence, and thus could apply to an infinite number of possible compounds.
The state of the prior art: The state of the art recognizes that there are hyperproliferative malignancies, including many rare cancers that are not curable. As disclosed by Pillai et. al., Indian J. Med. Res. 2017 Jan;145(1):17-27, “Many rare cancers in adults, adolescents and children are not curable, and patients and care providers have little option to take therapeutic decisions.” (Abstract).
Zhou et al., Journal of Molecular Cell Biology, Volume 11, Issue 4, April 2019, Pages 293–305, teaches the complexity associated with treating malignancies associated with mutant p53 and strategies targeting the mutation. Zhou teaches that although a growing number of strategies targeting mutant p53 for cancer therapy have been developed, cellular response to the mutant p53-targeting compounds may display considerable variation, because most agents are only specifically potent for several p53 mutants with regard to their distinct conformations and in different cellular contexts. Furthermore, like other anti-cancer agents, the mutant p53-targeting agents also have off-target activity that may cause mutant p53-independent adverse effect by triggering cytotoxicity in the normal cells (page 301).
Zhou et al., also teaches Applicant’s claimed method of combining APR-246 compound, for example, in combination with other therapies: “Of note, APR-246 displays a synergistic inhibitory effect on tumor growth in combination of several commonly used chemotherapeutic drugs (Bykov et al., 2005). It also cooperates with Sulfasalazine, Auranofin or Carfilzomib in eliciting cell death by exploiting the aforementioned mutant p53/NRF2-mediated oxidative or proteasomal signal (Walerych et al., 2016; Liu et al., 2017; Lisek et al., 2018).” Zhou et al., also states that “Some of these molecules in combination with the conventional therapies have been shown to greatly improve cancer treatment.” (pp. 299-300).
However, Applicant’s Specification primarily relies on in-vitro modeling to test synergy of various p53 inhibitors (c.f., p. 80, para. [00380]-[00383]), alongside making claim to all Bcl-2 inhibitors. Nowhere in the Specification is all Bcl-2 inhibitors, for example, in combination with p53 inhibitors supported or enabled, which also includes Bcl-2 inhibitors yet to be discovered.
“Contemporary pre-clinical development of anticancer agents – What are the optimal preclinical models?” by Damia et al., Eur. J. Cancer 45, 2768-81 (2009) discloses that, although the identification of new anti-cancer agents is mainly based on in vitro methodologies, in vivo models (i.e., whole animal models) are absolutely required to assess the pharmacological activity of a potential new drug (p. 2769). It is important to understand how a drug undergoes distribution in both neoplastic and normal tissues, as well as how it is metabolized and eliminated, before it is administered to humans (p. 2769). Often, the activity of a new compound depends not only on the intrinsic cellular sensitivity but also on other mechanisms related to the presence of the stroma, the hypoxic conditions, and neo-angiogenesis, among other factors that are present in vivo but not in vitro (p. 2769). As such, one cannot assume that just because a drug candidate shows activity in an in vitro assay that it will necessarily be useful in the pharmaceutical treatment of an actual cancer. While in vitro assays, both cell based and molecular target driven, are valuable for the identification of an active compound, in vivo studies are needed to assess actual anti-cancer activity (p. 2769). For example, pharmacological and toxicological studies are needed to define drug absorption, distribution, metabolism, and elimination and to ascertain a safe dose in humans (p. 2769). Applicant Specification solely describes two relevant Examples on pages 89 and 107, showing APR-246 p53 inhibitor in combination with two other therapeutics. Damia et al., teaches that, once it has been established by biochemical assays that the drug is effective and sufficiently potent and specific for its target, one must verify that its biological activity is related to the functional inhibition of the target in different cellular contexts (p. 2274). It is especially important that the drug be assayed in tumor targets of human origin (p. 2774). In vitro experimental models that are currently used for the identification and selection of novel anticancer drugs are far from being satisfactory in mimicking the complex biological features of human tumors (p. 2777). Even with the enormous advancement of knowledge in tumor biology, the expected improvement of the efficacy of cancer therapy has not resulted (p. 2777). Cancer comprises hundreds of different diseases, and each one is remarkably heterogeneous in different patients and even in the same patient during the progression of the disease (p. 2777). Therefore, to reproduce the complexity of human cancer with in vitro assays is not feasible (p. 2777).
Due to the complex nature of hyperproliferative malignancies, suggesting the combination of p53 inhibitors with inhibitors of Bcl-2 to treat all hyperproliferative malignancies based on Examples on pages 89 and 107 of Specification and synergetic models does not reasonably support enablement.
“Lack of in vitro - in vivo correlation of a novel investigational anticancer agent, SH 30” by Poondru et al., Invest. New Drugs 20, 23-33 (2002) discloses that, in solid tumors, the reasons for the lack of in vitro and in vivo correlation of drug activities are multifold and include permeability to the tumor cells, interstitial hypertension, and metabolic degradation (p. 23). It is imperative for successful anti-cancer therapy that the cytotoxic agent reaches the cancer cells in sufficient concentrations to produce therapeutic effects (p. 29). Two major barriers that can prevent a cytotoxic agent from achieving this include inability of the agent to permeate the multilayered tumor cells with formidable extracellular matrix and extensive inactivation by metabolic enzyme(s) that cause a short systemic half-life (p. 29). So, it is important to study the permeability and metabolic disposition of new compounds in order to determine whether such compounds are actual pharmacologically useful especially when combined (p. 23). In order to be useful, anti-cancer agents should have properties enabling rapid uptake by targeted tissue and minimum susceptibility to enzyme-mediated inactivation (p. 24).
The level of the skill in the art & The predictability in the art: The relative skill of those in the art is high, that of an MD or PHD. That factor is outweighed, however, by the unpredictable nature of the art. As illustrative of the state of the art, the examiner contends that the term hyperproliferative malignancy encompasses various type of cancers, the Bcl-2 inhibitors include those known and have yet been discovered, and yet applicant failed to provide enablement that supports the claim scope. Further, the predictability of treating many rare cancers, is relatively low given that the various types of cancers have different causative agents, involve different cellular mechanisms, and consequently, differ in treatment protocol. It is known (see Golub et al., Science, Vol. 286, October 15, 1999, pages 531-537) in the current art that the challenge of cancer treatment has been to target specific therapies to pathogenetically distinct tumor types, to maximize efficacy and minimize toxicity.
One skilled in the art would not reasonably expect that the method of combining p53 inhibitors and all Bcl-2 inhibitors would be effective in treating all hyperproliferative malignancies.
Thus, given that applicant has failed to provide support for the full enablement of the scope of the claims, and in light of the challenge in treating various types of cancers, the examiner maintains that applicant has not enabled the breadth of the claims. It is noted that the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity. In re Fisher, 427 F. 2d 833, 166 USPQ 18 (CCPA 1970) indicates that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute. They have not shown a nexus to treat diseases but have provided only reports in vitro which, absent a correlation to treat of diseases, are not sufficient to enable the invention.
The quantity of experimentation necessary, the amount of direction or guidance provided, the presence or absence of working examples: The amount of guidance or direction needed to enable the invention is inversely related to the degree of predictability in the art. In re Fisher, 839, 166 USPQ 24. Thus, although a single embodiment may provide broad enablement in cases involving predictable factors, such as mechanical or electrical elements, in cases involving unpredictable factors, such as most chemical reactions and physiological activity, more teaching or guidance is required. In re Fisher, 427 F.2d 839, 166 USPQ 24; Ex Parte Hitzeman, 9 USPQ 2d 1823. For example, the Federal Circuit determined that, given the unpredictability of the physiological activity of RNA viruses, a specification requires more than a general description and a single embodiment to provide an enabling disclosure for a method of protecting an organism against RNA viruses. In re Wright, 999 F.2d 1562-63, 27 USPQ2d 1575.
Applicant Examples start off by disclosing that “It is to be understood that exemplary descriptions written in the present tense were not necessarily performed, but rather that the descriptions can be performed to generate the data and the like associated with the teachings of the present invention. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, percentages, etc.), but some experimental errors and deviations should be accounted for…” (Specification, page 82). Applicant Specification solely describes two relevant Examples on pages 89 and 107. The Examples provided include safety study of a Phase I and II study of a single p53 inhibitor, already known in the art as described above by Zhou et al., in combination with some already known Bcl-2 therapeutics. No other guidance is provided.
The description and the Examples convey the impression that the claimed invention is carried out in a particular way, namely by the use of quinuclidine-3-one derivatives, in particular APR-246 and Compounds A-E, in combination with venetoclax/AMG176/MIK665. Therefore, the scope of claims are both unclear and broader than justified by the technical contents of the Specification.
Because of the known unpredictability of the art, and in the absence of experimental evidence, no one skilled in the art would accept the assertion that every instantly claimed p53 inhibitor could be predictably used in combination with all Bcl-2 inhibitors for the treatment of all hyperproliferative malignancy in a subject, inferred by the claims and contemplated by the specification. Accordingly, the instant claims do not comply with the enablement requirement of §112, since to practice the invention claimed in the patent a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success. One of ordinary skill in the art, even with high level of skill, is unable to use the instant compounds as claimed without undue experimentation. As pointed out by the court in In re Angstadt, 537 F.2d 498 at 504 (CCPA 1976), the key word is “undue”, not “experimentation”.
Claim Rejections - 35 USC § 112
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 2-4, 6, 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 claim 2, the claim recites functional language “… promotes proper folding…”, and “…restores at least part of a normal p53 function…”. The phrase “promote proper folding”, and “restores at least part of a normal p53 function” recite functional language, and do not allow for a clear definition of the structure of the claimed method which is drawn to a method of treating a hyperproliferative malignancy in a subject comprising administering to the subject a therapeutically effective amount of a compound that reactivates a mutant p53 and an inhibitor of an antiapoptotic Bcl-2 family protein. The phrase does not provide a clear-cut indication of the scope of the subject matter covered by the claim, and only states a result obtained. One of ordinary skill in the art would not know from the claim terms what structure or steps are encompassed by the claim.
The term “restores at least part of a normal p53 function” in claim 2 is also a relative term which renders the claim indefinite. The term “at least part of” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. This in turn renders the limitation of a normal p53 function indefinite. Moreover, what constitutes normal p53 function is unclear because subject is not limited and what is considered normal p53 function can vary from one subject to another (e.g., bird, reptile, cow, pig, horse p53 function vs. p53 function in a human).
Regarding claim 3, the claim recites in part: “… the compound that reactivates the mutant p53 is resting in a shift of the equilibrium from unfolded towards a wild-type like p53 conformation…”. The phrase “is resting in a shift of the equilibrium from unfolded towards a wild-type like p53 conformation…” recites functional language, and does not allow for a clear definition of the structure of the claimed method which is drawn to a method of treating a hyperproliferative malignancy in a subject comprising administering to the subject a therapeutically effective amount of a compound that reactivates a mutant p53 and an inhibitor of an antiapoptotic Bcl-2 family protein. The phrase does not provide a clear-cut indication of the scope of the subject matter covered by the claim, and only states a result obtained. One of ordinary skill in the art would not know from the claim terms what structure or steps are encompassed by the claim.
Regarding claim 6, the claim recites in part that the compound that reactivates the mutant p53 binds to thiol groups in the core domain of the mutant p53 and restores wild-type conformation. The claim scope as it relates to a method of treatment per claim 1 is unclear as claim 6 does not provide a clear-cut indication of the scope of the subject matter covered by the claim, and only states a result obtained. One of ordinary skill in the art would not know from the claim terms what structure or steps are encompassed by the claim as the claim merely amounts to a statement of the underlying problem without providing the technical features necessary for achieving this result.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 5-6 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 5 depends from independent claim 1 which recites the following:
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Claims 5-6 recite:
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The inclusion of a metabolite thereof, or a degradation product thereof broadens the scope of claim 5, which should be further narrowing of the scope of claim 1 from which it depends. Claim 6 is rejected also for its dependence on claim 5. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Interpretation
Claims 2-4 are rejected under 35 U.S.C. 112(b) as discussed above. Claims 2-4 are interpreted based on the limitation of claim 6 which states that the compound that reactivates the mutant p53 binds to thiol groups in the core domain of the mutant p53 and restores wild-type conformation. Any p53 inhibitor meeting this definition is considered to have met the limitations of claims 2-4.
Claim 30 recites:
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The claim is interpreted to mean two separate formulations comprising the respective inhibitors, that are then administered per the method of claim 1 wherein the treatment comprises administering to the subject a therapeutically effective amount of a compound that reactivates a mutant p53 and an inhibitor of an antiapoptotic Bcl-2 family protein.
Claim Rejections - 35 USC § 102
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.
Claims 1, 2-6, 8, 24, 30, 36, 38, and 48 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Cory et al., Anticancer Research March 2006, 26 (2A) 1289-1295 (“Cory”), and as evidenced by Lewis et al., Bioscience Horizons: The International Journal of Student Research, Volume 8, 2015, hzv006.
Regarding claims 1 and 48, Cory teaches a method of treating hyperproliferative malignancy in a subject comprising administering to the subject a therapeutically effect amount of a compound that reactivates a mutant p53 and an inhibitor of an antiapoptotic Bcl-2 family protein.
Cory et al., teaches the effects of PRIMA-1 on wild-type (WT) mouse leukemia L1210 cells and drug-resistant L1210 cells (Y8) with respect to the induction of apoptosis and necrosis in these cell lines. The WT L1210 cells express mutant p53 while the Y8 L1210 cells do not express p53 mRNA or protein. Cory teaches that “It was found that, in response to treatment with PRIMA-1, the WT L1210 cells became necrotic with little apoptosis while the Y8 L1210 cells showed a much higher level of apoptosis than necrosis…” (Abstract). The compound 2, 2-bis (hydroxymethyl)-1-azabicyclo[2,2,2] octan-3-one, designated as PRIMA-1, is known to reactivate p53 and induce apoptosis (Cory, page 1289).
Cory et al., also teaches in the Abstract that flavopiridol in combination with PRIMA-1 caused a synergistic increase in necrosis in the WT L1210 cells while LY 294002 in combination with PRIMA-1 caused a synergistic increase in apoptosis in the Y8 L1210 cells. Claims 1 and 48 are anticipated by Cory.
Regarding claims 2-4, Cory teaches the method of claim 1. Cory teaches that PRIMA-1 is known to reactivate p53 and induce apoptosis (Cory, page 1289). As discussed above in the claim interpretation, the limitations of claim 2-4 are interpreted such that any compound that reactivates a mutant p53 by binding to thiol groups in the core domain of the mutant p53 and restores wild type conformation meets the limitation.
While Cory does not expressly teach this feature, PRIMA-1 is known in the art to “…restore the mutant p53 by modifying thiol groups in the core domains of the protein…”, and “PRIMA-1 exploits the high occurrence of a mutated p53 protein in cancers and acts to restore the mutated protein to its wild-type state. The restored p53 can then resume its role inducing apoptosis to prevent superfluous cell proliferation…”, as evidenced by Lewis et al., Bioscience Horizons: The International Journal of Student Research, Volume 8, 2015, hzv006 (Abstract) and on page 2 discloses that: “One proposed mechanism of action is that the PRIMA-1MET covalently binds to and modifies thiol groups in the central domain of the mutated protein”. The claims are anticipated by Cory as evidenced by Lewis et al.
Regarding claims 5-6, Cory teaches the method of claim 1. The limitations that the compound that reactivates the mutant p53… restores a p53 wild type function by covalently binding to thiol groups in the core domain of the mutant p53 is anticipated by Cory, and evidenced by Lewis et al. PRIMA-1 as discussed by Cory binds and restores mutant p53.
While Cory does not expressly teach the feature that PRIMA-1 restores a p53 wild type function by covalently binding to thiol groups in the core domain of the mutant p53, PRIMA-1 is known in the art to “…restore the mutant p53 by modifying thiol groups in the core domains of the protein…”, and “PRIMA-1 exploits the high occurrence of a mutated p53 protein in cancers and acts to restore the mutated protein to its wild-type state. The restored p53 can then resume its role inducing apoptosis to prevent superfluous cell proliferation…”, as evidenced by Lewis et al., Bioscience Horizons: The International Journal of Student Research, Volume 8, 2015, hzv006 (Abstract) and on page 2 discloses that: “One proposed mechanism of action is that the PRIMA-1MET covalently binds to and modifies thiol groups in the central domain of the mutated protein”. The claims are anticipated by Cory as evidenced by Lewis et al.
Regarding claim 8, Cory teaches the method of claim 1. Cory also teaches the compound that reactivates the mutant p53 as 2, 2-bis (hydroxymethyl)-1-azabicyclo[2,2,2] octan-3-one, and also known as 2,2-bis(hydroxymethyl)quinuclidin-3-one. (Cory, page 1289).
Regarding claim 24, Cory teaches the method of claim 1. Cory teaches the inhibitor of an antiapoptotic Bcl-2 family protein, as flavopiridol, a Mcl-1 inhibitor (Abstract). The claim is also anticipated.
Regarding claim 30, Cory teaches the method of claim 1. Cory teaches that PRIMA-1 was combined with flavopiridol (c.f., Table IV. Necrotic effects of PRIMA-1 in combination with flavopiridol on WT L1210 cells) and discusses this in the Abstract. Per the claim interpretation above, and Cory’s teachings, claim 30 is also anticipated.
Regarding claim 36, Cory teaches the method of claim 1. Cory teaches the administration of PRIMA-1 and flavopiridol in the treatment of leukemia (c.f., Abstract). Claim 36 is also anticipated.
Regarding claim 38, Cory teaches the method of claim 1. Cory teaches the method in treating chronic lymphocytic leukemia (CLL): “Using clinical samples of chronic lymphocytic leukemia cells, it was found that PRIMA-1 acted either in an additive or synergistic manner with fludarabine…” (p. 1294).
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.
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.
Claims 7, 9, 15, 18, 28-29, 31-32, 43, and 49 are rejected under 35 U.S.C. 103 as being unpatentable over Cory et al., Anticancer Research March 2006, 26 (2A) 1289-1295 (“Cory”), as evidenced by Lewis et al., Bioscience Horizons: The International Journal of Student Research, Volume 8, 2015, hzv006, and as applied to claims 1, 2-6, 8, 24, 30, 36, 38, and 48 above, and in view of Zhang et al., Cell Death Dis 9, 439 (2018) (“Zhang”), Roberts et al., N Engl J Med 2016;374:311-322 (“Roberts”), and Paterson et al., WO 2018/236904 A1 (“Paterson”) as discussed below.
Regarding claim 7, Cory teaches the method as applied above to claim 1. Cory does not teach wherein the mutant p53 comprises at least one of the replacements R175H or R273H.
However, Zhang teaches in the Abstract that:
“The mutant p53 reactivating compound APR-246 (PRIMA-1Met) has been successfully tested in a phase I/IIa clinical trial. APR-246 is converted to the reactive electrophile methylene quinuclidinone (MQ), which binds covalently to p53 core domain. We identified cysteine 277 as a prime binding target for MQ in p53. Cys277 is also essential for MQ-mediated thermostabilization of wild-type, R175H and R273H mutant p53, while both Cys124 and Cys277 are required for APR-246-mediated functional restoration of R175H mutant p53 in living tumor cells.”
Zhang also “PRIMA-1 and the PRIMA-1 analog APR-246 (PRIMA1Met) …” are among several low molecular weight compound that have been reported to restore wild-type function to mutant p53 (p. 1). “PRIMA-1 was shown to promote R175H mutant p53 refolding to wild-type conformation in SKOV-His175 cells…” but this was not yet tested for APR-246 (pp. 5-6) according to Zhang and became part of the basis of their experiment. It would have therefore been prima facie obvious, before the effective filing date of the claimed invention, to include the claimed mutations in view of Cory and Zhang’s teaching, and arrive at the claimed invention with reasonable expectation of success. One would be motivated to do so because Zhang teaches R175H and R273H as common. The claim is therefore rejected under 35 U.S.C. 103 as being unpatentable over Cory et al., Anticancer Research March 2006, 26 (2A) 1289-1295 (“Cory”), as evidenced by Lewis et al., Bioscience Horizons: The International Journal of Student Research, Volume 8, 2015, hzv006, and as applied to claims 1, 2-6, 8, 24, 30, 36, 38, and 48 above, and further in view of Zhang et al., Cell Death Dis 9, 439 (2018) (“Zhang”).
Regarding claim 9, Cory teaches the method of claim 8 as discussed and applied above. Cory does not teach APR-246, an analog of PRIMA-1. However, as discussed above, Zhang teaches both “PRIMA-1 and the PRIMA-1 analog APR-246 (PRIMA1Met) …” (p. 1) as among several low molecular weight compound that have been reported to restore wild-type function to mutant p53 (p. 1, and Abstract). Claim 9 is also obvious.
Regarding claims 15 and 18, Cory teaches the method of claim 1 as discussed and applied above. Cory and Zhang’s teachings as it relates to PRIMA-1 and APR-246 are also discussed above.
Cory in view of Zhang does not teach the limitation of claim 15, wherein the inhibitor of an antiapoptotic Bcl-2 family protein is a venetoclax (ABT-199).
Roberts teaches in the Abstract that venetoclax selectively targets Bcl-2 in the treatment of relapsed chronic lymphocytic leukemia (CLL), and induces apoptosis. Roberts also teaches that despite the success of venetoclax, patients with certain deletions that result in “… loss of function of the tumor suppressor TP53 represents a major obstacle to successful therapy…” (p.320). Cory teaches the Bcl-2 inhibitor as flavopiridol; venetoclax represents another alternative Bcl-2 inhibitor.
To one of ordinary skill in the art, considering Cory and Zhang’s teachings regarding PRIMA-1, and APR-246 as known reactivators of p53 and inducers of apoptosis (Cory, page 1289; Zhang, page 1, 5 and 6), and Roberts teachings regarding p53 as a major obstacle to overcome when it came to improving the effectiveness of venetoclax in treating relapsed chronic lymphocytic leukemia (CLL), it would have been obvious before the effective filing date of the claimed invention, to combine the teachings of Cory, Zhang and Roberts and arrive at the claimed method with reasonable expectation of success. One would have been motivated to target two known critical tumor suppressor proteins, using known inhibitors of each protein and arrive at the claimed invention with reasonable expectation of success based on the prior art teachings. Additionally, obviousness does not require absolute predictability, but a reasonable expectation of success. See MPEP 2143.02.
Regarding claims 28 and 29, Cory teaches the method of claim 1. Cory in view of Zhang teaches APR-246 as the compound that reactivates p53 as discussed above. Roberts teaches venetoclax as an alternative Bcl-2 inhibitor to Cory flavopiridol Bcl-2 inhibitor.
Cory, Zhang and Roberts do not alternative Bcl-2 inhibitors such as the claimed AMG-176 and MIK665 per claims 28 and 29.
However, Paterson teaches inhibitors of an antiapoptotic Bcl-2 family proteins such as venetoclax, AMG-176, and MIK665 for use in treating hematological cancers (c.f., Paterson claims 1-8, and 54-56). Paterson also teaches the combined use of venetoclax and azacitidine (c.f., page 106, first paragraph).
To one of ordinary skill in the art, combining the teachings of Cory, Zhang, Roberts and Paterson to arrive at the claimed invention of alternative Bcl-2 inhibitors for use in the claimed method of treatment would have been obvious as discussed and applied above. Claims 28 and 29 are obvious.
Regarding claims 31-32, Cory teaches the method of claim 1 as discussed above. Cory, Zhang, Roberts, and Paterson’s teachings are also discussed above. Paterson teaches the combined use of venetoclax and azacitidine (c.f., page 106, first paragraph). The claims are obvious.
Regarding claim 43, Cory teaches the method of claim 1. However, Cory does not teach the claimed hyperproliferative malignancies per claim 43.
Zhang teaches the use of APR-246, the PRIMA-1 analog as well as PRIMA-1 in treating human lung adenocarcinoma, osteosarcoma, along with ovarian cancer cells (c.f., Cell lines and Reagents on page 9). Claim 43 is obvious.
Regarding claim 49, Cory teaches the method of claim 48. Cory in view of Zhang as disclosed above teach wherein the compound is APR-246. Claim 49 is also obvious.
Conclusion
No claims are allowed.
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/C A/ Examiner, Art Unit 1622
January 30, 2026
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622