DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
The instant application, filed on October 9, 2023, is a national stage entry of International Application No. PCT/IB2022/053282, filed April 7, 2022, which claims priority to Indian Provisional Patent Application No. 202141016598, filed on April 8, 2021. Receipt is acknowledged of certified copies of papers required by 37 CFR § 1.55.
Status of Claims
Applicants’ preliminary amendments received October 9, 2023, are acknowledged and entered.
Claims 2-5, 7-11, 13-17, 19-23, 25- 31, 33-54, 56-58, 61, 62 and 64 are canceled.
Claims 12, 18, 24, 32, 55, 59, 60, 63 and 65-69 are amended.
Claims 1, 6, 12, 18, 24, 32, 55, 59, 60, 63 and 65-69 are pending.
Information Disclosure Statement
The Information Disclosure Statement received on October 9, 2023, is acknowledged and found to be in compliance with the provisions of 37 CFR § 1.97. Accordingly, the Information Disclosure Statement has been considered.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 12, 18, 24 and 32 Do Not Comply with the Written Description Requirement
Claims 12, 18, 24, and 32 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
As explained below, the examiner finds that claims 12, 18, 24, and 32 are genus claims of potential salts of compound 1, and that the claims are not supported by the disclosure of a representative number of species falling within their scope.
The Claims
Claims 12, 18, 24, and 32 are each independent claims generally directed to crystalline salt forms of (R)-(+)-4-((5-(3-Hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one characterized by X-ray powder diffraction (“XRPD”) and/or differential scanning calorimeter (“DSC”) patterns.1 Applicants designate the aforementioned compound as compound 1, which the examiner will adopt for this portion of the rejection. The chemical structure of this compound is reproduced below.
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Specification at 4, paragraph [19].
Claim 12 is Exemplary of the Written Description Issues Common to Claims 12, 18, 24, and 32
Claim 12 recites:
A crystalline hydrochloride salt of (R)-(+)-4-((5-(3-Hydroxy-3-methyl-2-oxoindolin-l-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one, wherein the crystalline hydrochloride salt exhibits one or more of:
an X-ray powder diffraction pattern having one or more characteristic peaks at 5.32, 10.65, 14.91, 15.22, 16.68, 19.90, 21.75, 21.99, 23.84, 25.08, and 27.14 ± 0.2° 2θ;
an X-ray powder diffraction pattern substantially as depicted in Figure 5;
a differential scanning calorimeter pattern with a characteristic endothermic peak of about 228 °C; or
a differential scanning calorimeter pattern substantially as depicted in Figure 1.
Claim 12 (emphases added).
The claim is therefore structured as a genus claim where only “one or more of” the four alternative options a), b), c), or d) must be satisfied. Further, within option a), only “one or more” of the eleven listed “characteristic peaks” must present in the sample. Accordingly, it recites a genus of potential hydrochloride salts of compound 1, wherein at each option a), b), c), or d), multiple hydrochloride salts may be encompassed by the claim.
The Rules
Compliance with the written description requirement is a question of fact assed by determining “whether the disclosure of the application relied upon reasonably conveys to those skilled in the art that the inventor had possession of the claimed subject matter as of the filing date.” Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc) (internal citations and quotations omitted).
In Ariad, the Federal Circuit explained that the level of detail necessary to satisfy the written description requirement is dependent upon the context of the invention:
Thus, we have recognized that determining whether a patent complies with the written description requirement will necessarily vary depending on the context. Capon v. Eshhar, 418 F.3d 1349, 1357-58 (Fed.Cir.2005). Specifically, the level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology. Id. For generic claims, we have set forth a number of factors for evaluating the adequacy of the disclosure, including "the existing knowledge in the particular field, the extent and content of the prior art, the maturity of the science or technology, [and] the predictability of the aspect at issue." Id. at 1359.
Ariad, 598 F.3d at 1351.
In the context of genus claims, the court in Ariad further explains that possession of the claimed subject matter may be shown in a variety of ways, including by disclosing a representative number of species falling within the scope of the genus:
We held that a sufficient description of a genus instead requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can "visualize or recognize" the members of the genus. Id. at 1568-69. We explained that an adequate written description requires a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials. Id. at 1568 (quoting Fiers v. Revel, 984 F.2d 1164, 1171 (Fed.Cir.1993)). We have also held that functional claim language can meet the written description requirement when the art has established a correlation between structure and function. See Enzo, 323 F.3d at 964 (quoting 66 Fed.Reg. 1099 (Jan. 5, 2001)). But merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing that one has invented a genus and not just a species.
Ariad, 598 F.3d 1350 (citing Regents of the University of California v. Eli Lilly & Co., 119 F.3d 1559 (Fed.Cir.1997)); see also MPEP 2163 II.A.3.a.ii.
The Disclosure of a Single Crystalline Hydrochloride Salt of Compound 1
Applicants disclose the preparation and characterization of a single crystalline hydrochloride salt of compound 1 in Example 1A.2 Specification at 38-39. Here, Applicants describe how Compound 1A, i.e., the single crystalline hydrochloride salt of compound 1, was prepared by a process of crystallizing the free base (compound 1) in methanol acidified with hydrochloric acid. Compound 1A was characterized by the following measurements:
HCl content by titration: 10.31% (Theoretical: 8.39%). M.P.: 226-228°C. DSC: 228.33°C (Δ 67.36 J/g). 1H-NMR (δ ppm, DMSO-d6, 400 MHz) … DSC and XRPD diffractograms are provided in Figures 1 and 5.
The XRPD pattern of Compound 1A shown in Figure 5 (reproduced below) exhibits many peaks, including those matching the list provided in claim 12, viz., peaks at or around 5.32, 10.65, 14.91, 15.22, 16.68, 19.90, 21.75, 21.99, 23.84, 25.08, and 27.14 ± 0.2° 2θ). The DSC pattern of compound 1A shown in Figure 1 (reproduced below) shows an endothermic peak at 228.33°C with an enthalpy of Δ = 67.36 J/g.
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No other crystalline hydrochloride salt of compound 1 was described in the specification.3 Applicants do not discuss the reproducibility of their observations, any polymorph screening attempts, or whether any other crystalline hydrochloride salts of compound 1 exist.
The Breadth of Claim 12 – Option a)
Elementary combinatorics is helpful to highlight the breadth of this claim. Consider just the a) option, where a hypothetical species of claim 12 may meet the limitations for claim 12 if it matches one, or two, or all the way up to eleven of the recited XRPD peaks. The number of possible ways the hypothetical salt could meet the limitations of this claim element alone is represented by
∑
0
≤
k
≤
n
n
k
-
1
=
2
n
-
1
. For
n
of 11 total peaks, 211 – 1 equals 2047 possible combinations of peaks that satisfy option a) of claim 12 alone. However, as explained above, Applicants disclose only one possible species of claim 12 and it matches all of the peaks recited in claim 12. The remaining 2046 hypothetical combinations that match one or more of the 11 recited XRPD peaks, but not all 11 simultaneously, were not discussed in the specification in any manner.
Complexity and Predictability of the Relevant Technology
XRPD spectroscopy is considered the “gold standard” for characterizing many solid phases of matter.4 XRPD patterns of crystalline substances, such as drug substances, are often analogized to “fingerprints”, because each crystalline form of a compound produces a unique XRPD pattern tied to the exact crystal layout of the atoms in the crystalline form. See, e.g., Harry G. Brittain, X-ray Diffraction III: Pharmaceutical Applications of X-ray Powder Diffraction”, Spectroscopy, vol. 16, no. 7, pp. 14-18 (2001), hereinafter “Brittain 2001”, at 14 (“Because the majority of drug substances are obtained as crystalline powders, researchers often use the powder pattern of these substances as a readily obtainable fingerprint to determine structural type. In fact, it is only by pure coincidence that two compounds might form crystals for which the ensemble of molecular planes happen to be identical in all space.”).
Like fingerprint identification, where identification of a person based upon a fingerprint sample requires matching multiple points in the sample to a known reference in order to exclude the possibility of matching isolated points that overlap by coincidence, phase identification by XRPD requires matching multiple peaks to exclude the possibility of matching isolated peaks that may overlap by coincidence. As Brittain 2001 explains, “[t]he 1995 USP 23/NF 18 General Chapter on x-ray diffraction states that identity is established if the scattering angles of the 10 strongest reflections obtained for an analyte agree to within ±0.20 degrees 2-θ with that of the reference material….” Brittain 2001 at 15. This 10 strongest reflection rule of thumb for the qualitative phase identification has been maintained throughout the various iterations of the United States Pharmacopeia-National Formulary publication.5
Indeed, as Ivanisevic 2010 explains, “XRPD patterns are typically compared by overlaying and aligning the data from different samples.” Id. at 12. Ivanisevic 2010 further explains that
It is not uncommon for two patterns to share some but not all of the peak positions. This can be a coincidence or it can be due to one of the samples being a mixture of multiple phases, including the phase in the other sample. Experience and data from complementary experimental techniques are needed to resolve such ambiguous cases.
Ivanisevic 2010 at 12.
As an example, Ivanisevic 2010 at 12 provides the XRPD patterns for two distinct crystalline polymorphs of sulfamerazine in Figure 8, which is reproduced below. These patterns show substantial overlap and could be considered as “having one or more characteristic peaks” that are shared. However, as Ivanisevic 2010 explains, one must assess the entire pattern and not just isolated points. And even at that point, Ivanisevic 2010 remarks that “[t]here is insufficient information at this stage to designate either pattern as a polymorph of the material (e.g., they could be a solvate, hydrate, or a mixture of two or more polymorphs). However, it is clear that both materials are crystalline and structurally different.” Id. at 13.
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Identification of unique crystalline forms of drug substances is often critical to drug development. When the substance is crystallized by different processes, different crystal forms may, and often will, appear.6 Such forms are called “polymorphs”. In the pharmaceutical field, different polymorphic forms of the same underlying drug substance often shown advantageous or deleterious pharmacological properties. See, e.g., Ivanisevic 2010 at 11 (“ ‘Polymorphic forms of a drug substance can have different chemical and physical properties, including melting point, chemical reactivity, apparent solubility, disso-lution rate, optical and mechanical properties, vapor pressure, and density. These properties can have a direct effect on the ability to process and/or manufacture the drug substance and the drug product, as well as on drug product stability, dissolution, and bioavailability. Thus, polymorphism can affect the quality, safety, and efficacy of the drug product.’ ”).
However, during crystallization, the process by which the substance is crystallized has an unpredictable impact on the organization of the crystal lattice of the resulting crystals. See, e.g., Cruz-Cabenza 2015 at 8632 (“With no way of predicting if a molecule will crystallize, let alone in what forms or under what conditions, solid form screens are designed to broadly survey crystallization space in the hope of promoting different crystal nucleation and growth pathways.”). The following passage from Cruz-Cabenza 2015 exemplifies that while solid form screens are routine in drug development, their methods must be tailored to the particular underlying compound, their results are unpredictable, and in principle the number of possible solid form screens for a particular compound is infinite:
Regarding the search for polymorphs of a drug candidate the situation described by Caira in 1998 is still very much valid today: ‘‘Systematic investigation of a compound to determine whether it is prone to polymorphism... is routine practice in pharmaceutical pre-formulation studies.’’112 Across the industry, polymorph screening is routinely conducted during pre-clinical development to identify commercially viable solid forms, along with the forms that crystallization processes must be designed around and upon which control strategies for processing and storage of drug products are based.
The fact that polymorph screening is a component of the ‘‘routine’’ of research and development of a solid active pharmaceutical ingredient by no means implies that a particular polymorph screen is a routine procedure. There are no ‘‘cook book’’ recipes for carrying out such screens. As noted below every screen must be individually designed based on solvent, solubility, solvent mixtures, heating and cooling program, compound stability, amount of compound available and general familiarity with the compound and its physical and chemical properties.
The fiction that carrying out a crystal form search is a routine procedure has been propagated by some, notably in intellectual property circles.113 The complexities of any individual crystal form screen have recently been detailed by Myerson et al.114 While the crystal form screen is a component of the routine of drug product development, the crystal form screen itself for any particular compound is by no means routine.115 Many of the techniques used in solid form screening with widely variable timescales are shown in Fig. 5.114 In principle the number of possible experiments in a crystal form screen is infinite. In any particular case, for any particular compound the time and resources are finite, and the design and choice of suitable techniques and experiments depends on the skill and experience of the personnel dealing with that compound as well as familiarity with the vagaries of the compound.
Cruz-Cabenza 2015 at 8630.
Cruz-Cabenza 2015 concludes that “at least one in two compounds, when screened for polymorphs, displays polymorphism.” Id. at 8632. This finding extends to “salts”. Id. Further, while chiral molecules “appear less prone to being polymorphic than non-chiral molecules”, id. at 8632, three separate data sets showed that polymorphism was discovered in “26 ± 1%”, “45%”, and “61%” of the surveyed chiral compounds, id. at 8627.
In sum, Cruz-Cabenza 2015 concludes that the nature of polymorphism is unpredictable
Finally, with considerable effort to find the appropriate crystallization conditions, it appears that polymorphism may be as common as the lack thereof. While statistics may serve as a guideline, every compound presents a new system, and we still have no means of knowing without appropriate experimentation how many crystal forms can exist, how to prepare those unknown crystal forms, or once prepared, what their properties might be.
Many fictions have entered in the literature about the connection between the molecular nature of compounds and their propensity for polymorphism. Although we have shown that there may be some possible trends, the truth remains that polymorphism is unpredictable on the basis of molecular structure.
Cruz-Cabenza 2015 at 8632-8633 (emphasis added).
Claim 12 is not Supported by the Disclosure of a Representative Number of Species
The examiner finds that claim 12 is supported only by the disclosure of a single species of a crystalline hydrochloride salt of compound 1 described in Example 1A. This single species simultaneously satisfies all of the various permutations and options recited in the instant claim 12. That is, the Example 1A hydrochloride salt that Applicants designate as Compound 1A has an XRPD pattern having all of the characteristic peaks recited in option a), its XRPD pattern is depicted in Figure 5, it has a DSC pattern with a characteristic endothermic peak at 228.33 °C, and its DSC pattern is depicted in Figure 1.
The examiner further finds that Applicants provide no support for any other species of claim 12 outside of select ipsis verbis statements in the specification. See supra footnote 3. No other crystalline hydrochloride salt of compound 1 was described in the specification. Applicants do not discuss the reproducibility of their observations, any polymorph screening attempts, or whether any other crystalline hydrochloride salts of compound 1 exist. Applicants simply do not disclose any species of claim 12 wherein the crystalline hydrochloride salt exhibits less than the 11 recited XRPD “characteristic peaks” listed in option a).
As discussed above, the examiner finds that claim 12 is directed to a genus of hydrochloride salts of immense and indeterminate breadth. Based upon elementary combinatorics, claim 12, option a) has 2047 possible combinations of peaks that a species of claim 12 may exhibit. Exactly one disclosed compound, i.e., compound 1A, simultaneously satisfies all of these combinations. There is no disclosure of any compound that exhibits anything less than that.
Because Applicants did not disclose any attempts to screen polymorphic forms of crystalline hydrochloride salts of compound 1, one having ordinary skill in the art at the time of filing could not conclude that crystalline hydrochloride salts of compound 1 exhibit, or do not exhibit, polymorphism. However, the literature clearly states that compounds are more likely to exhibit polymorphism than not. See supra discussion of Cruz-Cabenza 2015 at 8632. The literature states that this phenomenon extends to salts of compounds, and that while chirality lessens the likelihood of polymorphism, a significant portion of chiral compounds still exhibit polymorphism. See supra discussion of Cruz-Cabenza 2015 at 8632 and 8627.
The unanswered question of polymorphism with respect to claim 12 is critical to the finding of a lack of written description support for the claim. If polymorphism indeed exists for hydrochloride salts of compound 1, the literature establishes that there is a significant likelihood that at least one XRPD “characteristic peak” may overlap between other polymorphic forms that Applicants disclosure shows no possession of. Such other polymorphic forms of hydrochloride salts of compound 1 that the instant inventors or others may later discover would be encompassed by the instant claim 12. Whatever advantageous or deleterious pharmacological properties derived from the “unpredictable” nature of polymorphism may thus be encompassed by the disclosure of a single crystalline hydrochloride salt of compound 1. This observation is not merely speculative, and is indeed reflected in Applicants’ own data.7 Whether or not Applicants’ own XRPD data are indicative of such compounds existing as “a solvate, hydrate, or a mixture of two or more polymorphs”, see supra discussion of Ivanisevic 2010 at 13, exemplifies why Applicants do not have support for sweeping all other potential crystalline hydrochloride salts of compound 1 into the instant claim based off an XPRD pattern having one overlapping “characteristic peak”. All that can be gleaned from one overlapping XRPD “characteristic peak” in view of an entire XRPD pattern as evidence by Ivanisevic 2010 at 13 “is … that both materials are crystalline and structurally different.” As such, Applicants have support to claim the species of a crystalline hydrochloride salt of compound 1 that was disclosed in the specification, and not for claiming an immense genus of indeterminate breadth of potential crystalline hydrochloride salts of compound 1 that were never disclosed and that Applicants’ specification shows no possession of.
Further complicating matters is that the broadest reasonable interpretation of claim terms recited in claim 12 drastically expand the breadth of the claim. For example, in option c) the claim term “about” is defined in the specification to mean that the recited number “may vary from, for example, between 1% and 15% of the stated number”. Specification at 23, paragraph [127]. Applying Applicants’ special definition for the term “about” to the instant claim 12 option c) results in the following claim language:
c) a differential scanning calorimeter pattern with a characteristic endothermic peak of, for example, between 1% and 15% 228 °C
15% of 228°C is ± 34.2°C.
Further, this range is open ended, due to the “for example” language. Nevertheless, the broadest reasonable interpretation of the range includes a “characteristic endothermic peak” between 193.8 °C and 262.2 °C.
Applicants disclose exactly one crystalline hydrochloride salt of compound 1 and its DSC pattern shows a “characteristic endothermic peak” at exactly 228.33 °C. There is no disclosure of any other “characteristic endothermic peak” for any other crystalline hydrochloride salt of compound 1.
Moreover, DSC, which is a thermal method, is considered a “complimentary technique” that “can be helpful in further characterizing drug products but only X-ray provides the necessary structural information to uniquely identify different polymorphs.” Ivanisevic 2010 at 11. “Fully characterizing any material requires the use of complementary techniques (thermal or spectroscopic) but X-ray is typically done first because it is fast, non-destructive, requires little material, and provides the necessary structural information.” Id. See also, id. at 13, discussing the overlapping XRPD patterns for sulfamerazine in Figure 8 (“Further characterization using for example, thermal methods (TGA, DSC) would confirm these materials are not solvates or mixtures but actual polymorphs and aid in determining the thermodynamically stable polymorph.”).
In view of Ivanisevic 2010, use of DSC may confirm the existence of polymorphs for crystalline hydrochloride salts of compound 1. Accordingly, option c) is broad enough to sweep in any polymorph that may later be discovered “having a characteristic endothermic peak” in its DSC pattern within an indeterminate temperature range. Such a hypothetical polymorph does not even have to exhibit an XRPD pattern having a single overlapping “characteristic peak” to get encompassed by this claim.
Further, Applicants own disclosure indicates that characterization based upon a single “characteristic endothermic peak” between 193.8 °C and 262.2 °C would encompass completely different salts from a crystalline hydrochloride salt of compound 1. See, e.g., instant Figures 2, 4A, 4B, 4D, and possibly 4C (depicting DSC patterns for benzene sulfonate and 4-methylbenzene sulfonate salts of compound 1 with “characteristic endothermic peaks” within the expressly contemplated range).
Applicants disclosure of a single “characteristic endothermic peak” at exactly 228.33 °C for a crystalline hydrochloride salt of compound 1 simply does not support the breadth of the recited range.
Furthermore, in options b) and d) the claim term “substantially” used in the context of “substantially as depicted” in a Figure, which is either a XRPD or DSC pattern, is a term of degree that is not defined in the specification. Accordingly, the broadest reasonable interpretation of these claim options encompass an indeterminate breadth of crystalline hydrochloride salts of compound 1 that produce XRPD or DSC patterns that are somehow “substantially” similar to the recited Figures. Applicants provide no disclosure of an XRPD or DSC pattern for crystalline hydrochloride salts of compound 1 other than that for compound 1A. Accordingly, Applicants only show possession of a single crystalline hydrochloride salt of compound 1 that produces XRPD and DSC patterns depicted in the instant Figures 5 and 1, respectively. The only deviation that Applicants disclosure supports is that which would be reasonably expected within the range of experimental error using the exact experimental conditions described in the specification used to obtain these data. See, e.g., Specification at 32-33, paragraphs [157] and [158] (describing the experimental conditions, such as temperature, instruments, and scan parameters for DSC and XRPD patterns). Applicants claim to crystalline hydrochloride salts of compound 1 that exhibit XRPD and DSC patterns “substantially as depicted” in two figures is simply too broad given the indeterminate breadth of the claim term recited.
Finally, underlying all of these issues is the fact that only one of the options a), b), c), or d) must be satisfied for a crystalline hydrochloride salt of compound 1 to get swept into the scope of the instant claim 12. If the salt does not exhibit a single matching “characteristic peak” on its XRPD pattern, its XRPD pattern may still be “substantially as depicted” in the instant Figure 5. If that does not occur, it may have a DSC pattern with “a characteristic endothermic peak” of 228 °C, and if that does not occur, it still might have “a characteristic endothermic peak” between 193.8 °C and 262.2 °C. Moreover, the claim language is of such indeterminate breadth that if the hypothetical salt’s DSC pattern has any “characteristic endothermic peak”, it gets swept into the instant claim. If none of that occurs, its DSC pattern may still be “substantially as depicted” in the instant Figure 1. Applicants disclosure of a single crystalline hydrochloride salt of compound 1 that simultaneously satisfies all of satisfies all of the various permutations and options recited in the instant claim 12 does not show possession the breadth of this claimed genus. Instead, the claim merely draws a fence around the outer limits of their purported genus.
Accordingly, claim 12 does not comply with the written description requirement. Applicants’ disclosure of a single crystalline hydrochloride salt of compound 1 shows possession of just that. Applicants are invited to amend the instant claim 12 in such a way to reduce its breadth commensurate with its support in the specification.
Claims 18, 24, and 32 are not Supported by the Disclosure of a Representative Number of Species
As stated above, claim 12 is exemplary to the written description issues common to claims 12, 18, 24 and 32. Briefly, the examiner will address the remaining claims.
Claim 18 recites a crystalline benzenesulfonate salt of compound 1, wherein the salt exhibits one or more of options (a), (b), (c), or (d). These options suffer same from the same issues as the instant claim 12. For example, option (a) requires just one matching XPRD “characteristic peak”, option (b) requires matching a XRPD pattern “substantially as depicted” in Figure 6, option (c) requires matching a DSC pattern with “a characteristic endothermic peak” of “about” 231 °C, and option (d) requires matching a DSC pattern “substantially as depicted” in Figure 2.
Applicants disclose a single crystalline benzene sulfonate salt of compound 1 that simultaneously satisfies all of satisfies all of the various permutations and options recited in the instant claim 18. See Specification at 39, Example 1B. Such a disclosure does not show possession the claimed genus.
Accordingly, claim 18 does not comply with the written description requirement for analogous reasons why claim 12 does not comply with the written description requirement. Applicants’ disclosure of a single crystalline benzene sulfonate salt of compound 1 shows possession of just that. Applicants are invited to amend the instant claim 18 in such a way to reduce its breadth commensurate with its support in the specification.
Claim 24 recites a crystalline mono-methylbenezne salt of compound 1, wherein the salt exhibits one or more of options (a), (b), (c), (d), (e), (f), or (g). These options suffer same from the same issues as the instant claim 12. For example, options (a) and (c) requires just one matching XPRD “characteristic peak”, options (b) and (d) requires matching a XRPD pattern “substantially as depicted” in Figure 7A or 7B, option (e) requires matching a DSC pattern with “a characteristic endothermic peak” of “about” 170 °C, option (f) requires matching a DSC pattern “substantially as depicted” in Figure 3, and option (g) requires matching one peak recited in option (c), now with a different level of experimental error, and a DSC pattern with “a characteristic endothermic peak” of “about” 170 °C.
Applicants disclose two crystalline 4-methylbenzene sulfonate salts of compound 1 that simultaneously satisfy all of satisfy all of the various permutations and options recited in the instant claim 24 in their collective (the examiner notes that DSC was provided for only a single 4-methylbenzene sulfonate salt, compound 1C, prepared by method 2, see Specification at 39-40, Example 1C). Such a disclosure does not show possession the claimed genus.
Accordingly, claim 24 does not comply with the written description requirement for analogous reasons why claim 12 does not comply with the written description requirement. Applicants’ disclosure of two crystalline 4-methylbenzene sulfonate salts of compound 1 shows possession of just that. Applicants are invited to amend the instant claim 24 in such a way to reduce its breadth commensurate with its support in the specification. The examiner recommends that Applicants separate claim 24 into two claims, one drawn to each disclosed crystalline 4-methylbenzene sulfonate salt of compound 1.
Claim 32 recites a crystalline methane sulfonate salt of compound 1, wherein the salt exhibits one or more of options (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l), (m), (n), (o), (p), (q), or (r). These options suffer same from the same issues as the instant claim 12. For example, options (a), (c), (e), and (g) requires just one matching XPRD “characteristic peak”, options (b) (d), (f), and (h) requires matching a XRPD pattern “substantially as depicted” in Figure 8A, 8B, 8C, or 8D, options (i), (j), (k), (m), (o), and (q) requires matching a DSC pattern with “a characteristic endothermic peak” of about a myriad of ranges spanning from about 172 °C to about 220 °C, and options (l), (n), (p), and (r) requires matching a DSC pattern “substantially as depicted” in Figures 4A, 4B, 4C, or 4D.
Applicants disclose four crystalline methane sulfonate salts of compound 1 that simultaneously satisfy all of satisfy all of the various permutations and options recited in the instant claim 32 in their collective. See Specification at 40-43, Example 1D. Such a disclosure does not show possession the claimed genus.
Accordingly, claim 32 does not comply with the written description requirement for analogous reasons why claim 12 does not comply with the written description requirement. Applicants’ disclosure of four crystalline 4-methylbenzene sulfonate salts of compound 1 shows possession of just that. Applicants are invited to amend the instant claim 32 in such a way to reduce its breadth commensurate with its support in the specification. The examiner recommends that Applicants separate claim 32 into four claims, one drawn to each disclosed crystalline methane sulfonate salt of compound 1.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 24 is Indefinite
Claim 24 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 24 is rejected under 35 U.S.C. 112(b) as indefinite because it is unclear if the recitation of a “mono-methylbenzene sulfonate salt” encompasses only the 4-methylbenzene sulfonate salt forms, such as described in the Specification derived from p-toluene sulfonic acid, see Specification at Example 1C,8 or if Applicants intend the scope of the claim to encompass all methyl benzenesulfonate salts.
Applicants are required to clarify the meaning of “mono-methylbenzene sulfonate salt” in the context of this claim.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Background – PARP Inhibitors
The subject matter of the instant claims are salts of two compounds, reproduced below.
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Specification at 4, paragraph [19].
Compound (1) is named (R)-(+)-4-((5-(3-Hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one; it is the enantiomer of compound (2). Specification at paragraph [07].
Compound (2) is named (S)-(-)-4-((5-(3-Hydroxy-3-methyl-2-oxoindolin-l-yl)pyridin-3-yl)methyl)phthalazin-l(2H)-one. Specification at paragraph [08].
The Specification explains that compounds 1 and 2 are poly(ADP-ribose) polymerase (“PARP”) inhibitors. Applicants state that at the time of filing, “Four [PARP inhibitors] are currently approved for clinical use: olaparib, rucaparib, niraparib, and talazoparib.” Id. (emphasis added).
By way of background, reference is made to Maddison Rose et al., “PARP Inhibitors: Clinical Relevance, Mechanisms of Action and Tumor Resistance”, Frontiers in Cell and Developmental Biology, vol. 8, pp. 1-22 (September 2020), hereinafter “Rose 2020”.
Rose 2020 explains that PARP inhibitors act by competing with NAD+ binding at the catalytic domains of PARPs:
Poly (ADP-ribose) polymerases (PARP) inhibitors (PARPi) are a class of anti-cancer drugs which compete with nicotinamide (NAD+) for the catalytically active site of PARP molecules.
Rose 2020 at 4.
Rose 2020 provides a schematic representation of several proposed mechanisms of action of PARP inhibitors, including olaparib:
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Rose 2020 at 3.
One proposed mechanism shown in the above figure is PARP Trapping, wherein PARP inhibitors competitively bind with NAD+ which results in PARP1 trapping and subsequent cell death.
It is well recognized that PARP activation is required at the site of stalled replication forks to facilitate MRE11-mediated restart of replication (Bryant et al., 2009; Koppensteiner et al., 2014). DNA DSBs are likely to arise following the collision of the replication fork with a DNA lesion or single strand break (Liao et al., 2018). Based on these findings, it was hypothesized that PARP inhibitors may induce tumor cell death because stalled replication forks are unable to be restarted in PARP inhibited homologous recombination repair-deficient cells. This is supported by the evidence that PARP inhibitors are synthetically lethal with tumors which possess either HR or fork stabilization defects (Liao et al., 2018).
The PARP trapping mechanism of PARP inhibitors is also linked to replication fork stalling and is one of the most well-established theories. This proposed mechanism also offers insight into why inhibiting PARP activity is significantly more cytotoxic than genetically removing PARP1 through methods such as small-interfering RNA(siRNA)technologies(Muraietal., 2012a). The initial PARP trapping theory proposed that PARP inhibitors competitively bind to the NAD+ binding domain on PARP1. This results in PARP1 becoming trapped on the DNA due to the inability to auto-PARylate PARP1 (Shen et al., 2013). There is strong evidence supporting this theory, including the observation that PARP1-DNA complexes pre-exposed to a PARPi had less ability to dissociate following NAD+ induced auto-modification of PARP1. Therefore, indicating that the PARPi mechanism could involve PARP trapping to some extent (Hopkins et al., 2015).
Given PARP1’s involvement in single strand break repair, it was proposed that PARP1 trapping results in a DNA lesion that cannot be bypassed by replication forks (Farmer et al., 2005). Subsequently, leading to the formation of DSBs and stalled replication forks at the site of damage, as the cell progresses through S-phase (Solier and Pommier, 2014). DSBs can only be repaired through homologous recombination (HR) repair or non-homologous end joining (NHEJ). As previously discussed, HR is essential for the error-free repair of DSBs and requires functional BRCA1/2 proteins (Offit, 2006; Palomba et al., 2014; Vos et al., 2018; Bu et al., 2019). In HR deficient tumors, such as BRCA1/2 mutated tumors, the inhibition of PARP yields DSBs which can only be repaired through NHEJ. NHEJ mediates the direct re-ligation of DNA lesions without the requirement of a homologous template. This direct re-joining increases the incidence of catastrophic genomic instability which may result in cell death. Furthermore, PARPi-induced collapsed replication forks cannot be repaired by NHEJ, resulting in death in HR deficient tumor cells (Figure 1b) (Min A. et al., 2013).
Rose 2020 at 7.
(continued on following page)
Claims 1, 6, 12, 18, 24, 32, and 55 are Obvious over WO’261 in view of Peddibhotla 2009, Yu 2016, Zhu 2012, Patani 1996, and Berge 1977
Claims 1, 6, 12, 18, 24, 32, and 55 are rejected under 35 U.S.C. 103 as being unpatentable over WO’261,9 in view of Peddibhotla 2009,10 Yu 2016,11 Zhu 2012,12 Patani 1996,13 and Berge 1977.14
Claims 1 and 6 are generally directed to the hydrochloride, benzenesulfonate, 4-methyl benzenesulfonate, and methanesulfonate salts of the enantiomers 1 and 2, reproduced below. The Specification explains that enantiomers 1 and 2 are inhibitors of poly(ADP-ribose) polymerase (“PARP”). Specification at 1, paragraph [05].
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The chemical structures of enantiomers 1 and 2 bear three readily identifiable parts (depicted below):
a 1(2H)-phthalazinone ring, which is connected by a methylene (CH2) unit to the meta position of
a 6 membered aromatic ring (in particular, a pyridine), which is connected at the other meta position to
a benzofused γ-lactam (in particular, a 3-substituted-3-hydroxy-2-oxindole).
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While the instant salts of the enantiomers 1 and 2 lack explicit disclosure in the art prior to the effective filing date of the instant application, WO’261 discloses their underlying phthalazinone – aryl – benzofused γ-lactam scaffold and its use for inhibiting PARP.
For example, WO’261 at 64 discloses the below Example 1 compound, which bears a γ-lactam (2-pyrrolidone) connected the phthalazinone – aryl portions of the above scaffold. The Example 1 compound has a mammalian PARP IC50 of less than 0.30 μM. WO’261 at 119.
As WO’261 explains in the genus discussed shortly below, when the γ-lactam of the Example 1 compound is fused with a benzene at C3,C4 of the 2-pyrrolidone ring, the resulting oxisoindole exhibits inhibition of the activity of PARP (see right path, below figure).15
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However, the genus disclosed in WO’261 does not explicitly teach the path chosen by Applicants, i.e., the Example 1 compound fused with a benzene at C4,C5 of the 2-pyrrolidone ring, resulting in an oxindole (see left path, above figure).
Turning to the above mentioned genus, WO’261 discloses the following 4-methylarylphthalazin-1(2H)-one scaffold that encompasses the Example 1 compound and explains that when the Example 1 compound is fused with a benzene at C3,C4 of the 2-pyrrolidone ring, the resulting oxisoindole exhibits inhibition of the activity of PARP. See WO’261 at 4-5:
Following further study, the present inventors have discovered that the following classes of derivatives of 1 ( 2H) -phthalazinone and related compounds also exhibit inhibition of the activity of PARP.
The first aspect of the present invention provides A compound of formula:
[AltContent: textbox (phthalazinone portion)][AltContent: ]
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[AltContent: textbox (6 membered aromatic ring portion)]or an isomer, salt, solvate, chemically protected form, or prodrug thereof, wherein:
A and B together represent an optionally substituted, fused aromatic ring;
[AltContent: ]RL is a C5-7 aryl group substituted in the meta position by the group R2, and optionally further substituted;
[AltContent: textbox (Benzofused γ-lactam portion)][AltContent: ]wherein R2 is …
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wherein:
n is 0…;
Y is … CRC1RC2;
RC3, RC4 … are independently selected from H…
…
and … RC7 and RC1 together with the carbon atoms to which they are attached form an optionally substituted ring system.
WO’261 at 4-5 (emphases added).
When Y is CRC1RC2 and n is zero, WO’261 provides the following structure for R2.
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WO’261 at 6.
When RC7 and RC1 together with the carbon atoms to which they are attached form an optionally substituted ring system, WO’261 explains that benzene is a preferred embodiment of the ring fused to the γ-lactam. This benzofused γ-lactam results in an oxisoindole moiety:
The term "fused ring system" as used herein pertains either to a system comprising in addition to the ring already defined in the formula, one or more aromatic rings, or one or more aliphatic rings.
The aromatic ring fused to the core rings, i.e. that formed by … RC7 and RC1 … may comprise solely carbon atoms…. The aromatic ring(s) preferably have five or six ring atoms.
WO’261 at 8-9.
WO’261 further discloses that the central C5-7 aryl group substituted in the meta position may be a pyridine with the connection Applicants use for the instantly claimed enantiomers 1 and 2:
Substituted in the meta position: The term "substituted in the meta position" as used herein, pertains to the substitution of the C5-7 aryl group in a position 2 atoms away from where the group is bonded to the central moiety by -CH2-. The following groups, which are given by way of example only, illustrate this position by the use of an asterix:
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WO’261 at 17-18 (the Examiner marked the C5-7 aryl group substituted in the meta position used to construct the instantly claimed enantiomers 1 and 2).
Accordingly, while WO’261 discloses the underlying phthalazinone – aryl – benzofused γ-lactam scaffold used to construct the instantly claimed enantiomers 1 and 2, it does not explicitly teach the benzofused γ-lactam in the form of a 3-substituted-3-hydroxy-2-oxindole motif.
However, one having ordinary skill in the art at the time of filing seeking to design an alternative PARP inhibitor would be motivated to substitute the oxisoindole of the phthalazinone – aryl – benzofused γ-lactam scaffold disclosed in WO’261 with a 3-substituted-3-hydroxy-2-oxindole, because the 3-substituted-3-hydroxy-2-oxindole motif is a recognized “privileged” motif in drug discovery and design programs that is known to impart anticancer properties in drug substances (Peddibhotla 2009 and Yu 2016).
Further, one having ordinary skill in the art at the time would have a reasonable expectation of success in inhibiting PARP with a compound constructed from the phthalazinone – aryl – benzofused γ-lactam scaffold disclosed in WO’261 wherein the benzofused γ-lactam is a 3- methyl-3-hydroxy-2-oxindole because the 3-methyl-3-hydroxy-2-oxindole maintains the 2-pyrrolidone structural element known to access the catalytic domain of PARP enzymes (WO’261, Zhu 2012, and Patani 1996).
Peddibhotla 2009
Peddibhotla 2009 reviews the 3-substituted-3-hydroxy-2-oxindole scaffold’s roles in biological systems and its applications in anticancer and other therapies:
Natural products and small molecules inspired by them are enjoying a resurgence of interest because they intersect biological space effectively and selectively. On account of their unprecedented structural diversity and biological activities oxindole natural products continue to attract the interest of chemists and biologists alike. Quarternary or spirocyclic 3-alkyl(aryl)-3-hydroxy-2-oxindole scaffold is at the core of several natural products with a wide spectrum of biological activities. Convolutamydines, arundaphine, donaxaridine, maremycins, paratunamide, celogentin K, TMC-95A-D, neuroprotectin B, flustraminol A and B, 3-hydroxy welwitindolinones and pyrrolidinoindoline-type alkaloid, CPC-1 are some examples of a growing list of bioactive 3-substituted-3-hydroxy-2-oxindole natural products. Simultaneous with the extraordinary progress in the development of selective synthetic methods, a number of drug discovery programs have now started to recognize the importance of this ‘privileged’ scaffold, because of the potent anti-oxidant, anti-cancer, anti-HIV, neuroprotective and other biological properties and diverse modes of action of this class of natural products and analogs inspired by them. There is strong impetus for the continued synthesis of novel diversity libraries based on the 3-substituted-3-hydroxy-2-oxindole core for the potential treatment of proliferative and other diseases and a clear understanding of underlying cellular pathways involved. In fact, this process is well underway as exemplified by the recent synthesis of novel spirocyclic tetrahydrofuran- and isoxazolidine-2-oxindole libraries capable of achieving growth inhibition of lung adenocarcinoma (A549) cells, hepatocellular carcinoma (HepG2) cells and human breast cancer cell line, MCF-7. This review covers the isolation, diverse structure, activity, synthesis, and known medicinal chemistry of 3-substituted-3-hydroxy-2-oxindoles.
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Peddibhotla 2009 at Abstract (emphases added).
Peddibhotla 2009 at 21 reviews the anticancer modes of action of the 3-substituted-3-hydroxy-2-oxindole scaffold found in natural products:
Natural products present a dazzling array of diverse chemical functionality and properties [1]. Since they have co-evolved with their putative biological targets, natural products intersect biological space effectively (potency) and perturb its function (target) in a highly controlled manner (selectivity) [2,3]. It is not surprising then that natural products have endured as promising leads for drug discovery [4-7]. On account of their unprecedented structural diversity and biological activities oxindole natural products have continued to attract the interest of chemists and biologists alike and have been the subject of excellent reviews [8,9]. 3-substituted-3-hydroxyoxindoles belong to a less studied but equally impressive sub-class of oxindole natural products, which has not been the subject of a review to date. The 3-substituted-3-hydroxy-2-oxindole scaffold is being continuously discovered to be at the core of several natural products with a wide spectrum of biological activities (see Section 1 and table 1).
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Peddibhotla 2009 at 21 (emphasis added).
Peddibhotla 2009 at 21-23 discusses antioxidant, anticancer, and cytokine modulating properties of several of the simplest 3-alkyl-3-hydroxyoxindoles found in nature, which are exemplified in Figure 1 (excerpted to the right):
Peddibhotla 2009 further reviews the application of such 3-substituted-3-hydroxy-2-oxindole scaffolds to cancer chemotherapies, wherein the various chemotherapies showed effectiveness against melanoma, leukemia, human non small cell lung, human breast, and human CNS cancer cell lines. See Peddibhotla 2009 at 31-33.16
Peddibhotla 2009 further explains that the diverse biological activities of compounds incorporating such scaffolds are extremely sensitive to the substitution pattern and the absolute configuration of the 3-position:
3-Alkenyl- and 3-arylsubstituted 3-hydroxyoxindoles, and derivatives thereof, have been used in a number of recent pharmaceutical studies. Biological activities were found to be extremely sensitive to the substitution pattern of the 3- alkyl/3-aryl substituent or the 3, 3’-spirocycle as well as the absolute configuration of the stereogenic center. Further examples presented here demonstrate how new structural diversity can be built into ‘privileged’ scaffolds such as 3-hydroxyoxindoles to achieve either more potent or diverse biological activities.
Peddibhotla 2009 at 31 (emphasis added).
Yu 2016
Yu 2016 expands upon the earlier Peddibhotla 2009 review of 3-substituted-3-hydroxy-2-oxindole scaffolds to discuss synthetic methods for unlocking various 3-hydroxyoxindoles, and remarks that oxindole scaffolds are privileged scaffolds in new drug discovery:
Oxindole scaffolds are prevalent in natural products and have been recognized as privileged substructures in new drug discovery. Several oxindole-containing compounds have advanced into clinical trials for the treatment of different diseases. Among these compounds, enantioenriched 3-hydroxyoxindole scaffolds also exist in natural products and have proven to possess promising biological activities. A large number of catalytic asymmetric strategies toward the construction of 3-hydroxyoxindoles based on transition metal catalysis and organocatalysis have been reported in the last decades. Additionally, 3-hydroxyoxindoles as versatile precursors have also been used in the total synthesis of natural products and for constructing structurally novel scaffolds. In this review, we aim to provide an overview about the catalytic asymmetric synthesis of biologically important 3-substituted 3-hydroxyoxindoles and 3-hydroxyoxindole-based further transformations.
Yu 2016 at Abstract (emphasis added).
In particular, Yu 2016 focuses on the impact of the chirality of the oxindole on the observed biological activity:
Chiral oxindoles are an important class of compounds, which widely exist in nature and have exhibited diverse biological ac-tivities [1-7]. Of particular interest are optically active 3-hydroxyoxindoles (also known as 3-hydroxyindolin-2-one and 3-hydroxy-2-oxindole), which are also prevalent in natural products and biologically important molecules (Figure 1). 3-Hydroxyoxindole-containing derivatives have recently drawn extensive attention due to their diverse biological activities [8]. Several 3-hydroxyoxindole-derived compounds are undergoing preclinical evaluation. For example, the well-known natural product TMC-95A is able to inhibit proteasome non-covalently and reversibly [9]. SM-130686 is currently being used for the treatment of growth hormone deficiency as a potent and orally active GHSR agonist [10]. YK-4-279 can potently inhibit the growth of Ewing’s sarcoma by blocking the interaction be-tween the oncogenic protein EWS-FLI1 and RNA helicase A (RHA) [11]. Interestingly, only (S)-YK-4-279 has been re-ported to be able to inhibit the EWS-FLI1/RHA interactions specifically, significantly more potent than its (R)-enantiomer and racemic compound [12]. Additionally, the 3-hydroxyoxin-doles as versatile intermediates have also been used to construct small-molecule libraries for drug screening.
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Yu 2016 at 1000-1001 (emphasis added).
Yu 2016 further emphases the use of 3-substituted-3-hydroxy-2-oxindole scaffolds for inhibiting the growth of human cancer cells:
3-Hydroxyoxindole scaffolds are prevalent in natural products and biologically relevant molecules, and have exhibited diverse biological activities such as inhibition of proteasome, antago-nizing GHSR and inhibiting growth of human cancer cells. Interestingly, for some 3-hydroxyoxindoles (e.g., YK-4-279 in Figure 1), different enantiomers display a remarkably different activity.
Yu 2016 at 1036 (emphasis added).
Zhu 2012
Zhu 2012 generally discloses structure activity relationship (“SAR”) studies of a series of tetrahydropyridopyridazinone PARP inhibitors bearing a general structure of chemical 8:
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Zhu 2012 at 4638.
Zhu 2012 provides the structures of PARP inhibitors in clinical trials at the time of publication of the article, and in particular, discloses the X-ray co-crystal structure of veliparib (green) overlaid with the proposed binding mode of compound 8c (yellow) to the PARP-1 catalytic domain:
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Zhu 2012 at 4636, Figs. 1 and 2.
Zhu 2012 explains that 1) the tetrahydropyridopyridazinone portion of compound 8c binds the catalytic domain of PARP-1 in a similar manner to olaparib, although the binding of 8c is further mediated by a hydrogen bond from the 5-NH to Glu-988, and 2) the pyrrolidinone carbonyl enhances potency through favorable interaction with the “northern pocket” of the catalytic domain:
Figure 2 displays an X-ray co-crystal structure of veliparib (1c) overlaid with a tetrahydropyridopyridazinone PARP inhibitor (8c). Consistent with our previous reports,9 as well as others, three key hydrogen-bond interactions between the carboxamide group of veliparib with Ser-904 and Gly-863 in the PARP-1 catalytic domain were observed. The carboxamide group was restricted into an opti-mal orientation for the hydrogen-bond interaction through forma-tion of an intramolecular hydrogen bond with the 3-nitrogen of the imidazole moiety. In addition to a characteristic p-stacking inter-action for PARP inhibitors between the benzimidazole ring and Tyr-907, the 1-NH of the benzimidazole ring appears to be in-volved in a water-mediated hydrogen bond (W1) with Glu-988 of the protein. While olaparib (1b) has demonstrated certain suc-cess in clinical trials, an overlay (not shown in the figure but sim-ilar to 8c) with veliparib shows that this compound lacks a hydrogen bond donor as for the ‘‘NH’’ of veliparib benzimidazole that forms a hydrogen bond interaction with W1. As modeling sug-gests in Figure 2, the proposed tetrahydropyridopyridazinone, in which a 5-NH is incorporated into the ring structure, would pro-vide additional molecular interaction as compared to olaparib. There is also a water molecule in the vicinity of the pyrrolidine-NH near the ‘‘northern pocket’’, displacement of this W2 with a pyrrolidinone carbonyl would increase the potency through poten-tial interaction with Tyr896. We have chosen a fluorine atom at the para-position of the 4-benzyl group as for the case of olaparib due to a limited space available at this position in the X-ray structure.
Zhu 2012 at 4636 (emphasis added).
Patani 1996
Patani 1996 explains that bioisosteres are interchangeable chemical atoms or groups that are expected to affect the same pharmacological target in the same way:
The widespread application of the concept of iso-sterism to modify biological activity has given rise to the term bioisosterism. As initially defined by Friedman,2 bioisosteres were to include all atoms and molecules which fit the broadest definition for iso-steres and have a similar type of biological activity, which may even be antagonistic. More recently this definition has been broadened by Burger as “Com-pounds or groups that possess near-equal molecular shapes and volumes, approximately the same distri-bution of electrons, and which exhibit similar physi-cal properties...”.5 The critical component for bio-isosterism is that bioisosteres affect the same phar-macological target as agonists or antagonists and, thereby, have biological properties which are related to each other.
Patani 1996 at 3148 (emphasis added).
Patani 1996 explains that fluorine is a common bioisostere of hydrogen, see, e.g., Patani 1996 at 3148-3150, and 3152, and that nitrogen is a common trivalent bioisostere of carbon, see, e.g., Patani 1996 at 3156, 3158, and 3159-3160.
Compounds 1 and 2 were Obvious at the Time of Filing
As a preliminary matter, addressing why claims 1 and 6 were obvious at the time of filing requires first addressing that compounds 1 and 2 were obvious at the time of filing. This portion of the rejection sets forth that it was obvious to modify the scaffold disclosed in WO’261 by substituting an oxisoindole with a particular oxindole to take advantage of the known therapeutic benefits that the particular class of oxindoles imparts. Further, it sets forth that there was a reasonable expectation of success in competitively binding the PARP-1 catalytic domain with such a compound, therefore solving the underlying motivation to prepare alternative PARP inhibitors.
First, WO’261 clearly discloses that the activity of mammalian PARP is significantly inhibited by the phthalazinone – aryl – benzofused γ-lactam scaffold when the benzofused γ-lactam is an oxisoindole. See 1) the genus discussed above that discloses such compounds inhibit the activity of mammalian PARP, and 2) the Example 8 compound bearing an oxisoindole in the form of a phthalimide that inhibits mammalian PARP with an IC50 of less than 0.30 μM. WO’261 at 119. See right path in the below figure.
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One having ordinary skill in the art at the time of filing would instantly recognize that the scaffold could be modified to instead incorporate an oxindole by fusing a benzene at C4,C5 of the γ-lactam (i.e., the 2-pyrrolidine ring of the Example 1 compound) while maintaining activity towards mammalian PARP because the 2-pyrrolidine ring moiety is conserved by such a modification (see left path, first step in the above figure).17 Once recognizing that the scaffold could be modified in such a way to incorporate an oxindole while maintaining activity towards mammalian PARP, one having ordinary skill in the art would be strongly motivated to incorporate an oxindole in the form of a 3-substituted-3-hydroxy-2-oxindole because Peddibhotla 2009 explains that “[t]here is strong impetus for the continued synthesis of novel diversity libraries based on the 3-substituted-3-hydroxy-2-oxindole core for the potential treatment of proliferative and other diseases….” Peddibhotla 2009 at Abstract (emphases added). Peddibhotla 2009 explains that this “strong impetus” arises because “drug discovery programs have now started to recognize the importance of this ‘privileged’ scaffold, because of the potential anti-oxidant, anti-cancer, anti-HIV, neuroprotective and other biological properties and diverse modes of action of this class of natural products and analogs inspired by them.” Id (emphases added). Therefore, one having ordinary skill in the art at the time of filing would be strongly motivated to replace the oxisoindole of the phthalazinone – aryl – benzofused γ-lactam scaffold taught by WO’261 with a 3-substituted-3-hydroxy-2-oxindole to increase the anticancer activity of the resulting PARP inhibitor.
However, one having ordinary skill in the art at the time of filing would recognize that the chirality and substitution pattern of the 3-substituted-3-hydroxy-2-oxindole moiety incorporated into the scaffold disclosed in WO’261 would impact the resulting biological activity of the PARP inhibitor because Peddibhotla 2009 teaches that the “[b]iological activities [of other 3-substituted-3-hydroxy-2-oxindoles] were found to be extremely sensitive to the substitution pattern of the 3- alkyl/3-aryl substituent or the 3, 3’-spirocycle as well as the absolute configuration of the stereogenic center.” Peddibhotla 2009 at 31 (citation modified in brackets for clarity).
Therefore, one having ordinary skill in the art at the time of filing would review the structure activity relationship (“SAR”) studies of similar phthalazinone – aryl – γ-lactam compounds in PARP enzymes to assess whether there was a reasonable expectation of success in inhibiting PARP by competitively binding the PARP catalytic domain with a compound incorporating a 3-substituted-3-hydroxy-2-oxindole moiety into the scaffold disclosed in WO’261, and arrive at Zhu 2012. One having ordinary skill in the art would have a reasonable expectation of success in competitively binding the PARP catalytic domain with a compound incorporating a 3-substituted-3-hydroxy-2-oxindole moiety into the scaffold disclosed in WO’261 because Zhu 2012 discloses:
the structure of compound 8c, which shares a similar scaffold to the WO’261 compound 1 (tetrahydropyridopyridazinone v. phthalazinone, and aryl-F as a bioisostere of H (see, e.g., Patani 1996 at 3148-3150, and 3152)),
the finding that the tetrahydropyridopyridazinone unit of 8c and the phthalazinone unit of olaparib bind the PARP-1 catalytic domain in the similar manner through Ser-904 and Gly-863 hydrogen-bonds, and
the finding that the 2-pyrrolidine carbonyl of 8c advantageously binds the “northern pocket” of the PARP-1 catalytic domain which enhances potency.
Accordingly, one having ordinary skill in that art at the time of filing would have a reasonable expectation that 1) the WO’261 Example 1 compound would bind the PARP-1 catalytic domain in a similar manner as the Zhu 2012 8c compound, and 2) the enhanced binding potency imparted through the 2-pyrrolidine carbonyl interaction with the “northern pocket” would extend to the oxindole and 3-substituted-3-hydroxy-2-oxindole variants that conserve the 2-pyrrolidine carbonyl (see left path, above figure).
Further, one having ordinary skill in the art at the time of filing would have a reasonable expectation of success in competitively binding the PARP-1 catalytic domain with the resulting structure, which:
further incorporates a benzene fused at C4,C5 of the 2-pyrrolidine ring, because WO’261 discloses that the closely structurally related Example 8 compound, which has a benzene fused at C3,C4 of the 2-pyrrolidine ring, significantly inhibits the activity of mammalian PARP, and
further incorporates an aromatic ring nitrogen in the form of a pyridine as the central C5-7 aryl group substituted in the meta position by the 3-substituted-3-hydroxy-2-oxindole, because
WO’261 discloses such modification of the scaffold exhibits inhibition of the activity of PARP, and
Patani 1996 explains that such aromatic ring nitrogens are trivalent ring equivalent bioisosteres of aromatic ring carbons (i.e., phenyl and pyridyl are bioisosteres, see, e.g., Patani 1996 at 3160).18
Turning to the 3-substituent of the 3-substituted-3-hydroxy-2-oxindole, one of ordinary skill in the art at the time of filing would have a reasonable expectation of success in competitively binding the PARP-1 catalytic domain by choosing a substituent that
minimized the steric bulk that would occupy the “northern pocket”, because Peddibhotla 2009 at 31 teaches that the biological activity of the resulting 3-substituted-3-hydroxy-2-oxindole is extremely sensitive to the substitution pattern of the 3- alkyl/3-aryl substituent, and
mimicked the substitution pattern of a known natural 3-substituted-3-hydroxy-2-oxindole showing promising anti-cancer properties, because Peddibhotla 2009 teaches such natural products “co-evolved with their putative biological targets, … intersect biological space effectively (potency) and perturb its function (target) in a highly controlled manner (selectivity)” and have “endured as promising leads for drug discovery.” Peddibhotla 2009 at Abstract (emphasis added).
One having ordinary skill in the art at the time of filing would therefore review the natural products and recognize that the convolutamydines exhibit anti-cancer properties while maintaining small 3-substituents (see (R)-convolutamydine C, reproduced below from Peddibhotla 2009 at 22, Figure 1, wherein the 3-substituent is methyl).
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Accordingly, one of ordinary skill in the art at the time of filing would have a reasonable expectation of success in competitively binding the PARP-1 catalytic domain by selecting methyl as the 3-substituent of the 3-substituted-3-hydroxy-2-oxindole because the selection minimizes steric bulk and mimics the substitution pattern of a natural 3-substituted-3-hydroxy-2-oxindole showing promising anticancer properties.
Therefore, a racemic mixture of the instant enantiomers 1 and 2 was obvious at the time of filing because one having ordinary skill in the art at the time of filing would have a reasonable expectation of success in competitively binding the PARP-1 catalytic domain with a racemic mixture the instant enantiomers 1 and 2 for the reasons stated above.
Furthermore, one having ordinary skill in the art at the time of filing would be strongly motivated to resolve the racemic mixture of the instant enantiomers 1 and 2 into the pure (R) and (S) forms because Yu 2016 explains that “enantioenriched 3-hydroxyoxindole scaffolds also exist in natural products and have proven to possess promising biological activities.” Yu 2016 at Abstract (emphasis added). Accordingly, one of ordinary skill in the art at the time of filing through the process of ordinary and routine optimization of the biological activity of lead compounds in drug discovery would have a reasonable expectation of success in resolving the racemic mixture of the instant enantiomers 1 and 2 into the pure (R) and (S) forms, and therefore arrive at the pure instant enantiomers 1 and 2.
Claims 1 and 6 were Obvious at the Time of Filing
The above section regarding that compounds 1 and 2 were obvious at the time of filing is incorporated herein.
Regarding pharmaceutically acceptable salts, WO’261 discloses that for compounds derived from the phthalazinone – aryl – benzofused γ-lactam scaffold of WO’261:
It may be convenient or desirable to prepare, purify, and/or handle a corresponding salt of the active compound, for example, a pharmaceutically-acceptable salt. Examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. Sci., Vol. 66, pp. 1-19.
WO’261 at 28.
Berge 1977 (i.e., Berge et al., referenced in the passage immediately above) at 2, Table 1, explains that benzenesulfonate salts are pharmaceutically acceptable salts.
WO’261 further discloses pharmaceutically acceptable salts of the PARP inhibitors may be derived from hydrochloric acid (hydrochloride), toluenesulfonic acid (4-methyl benzenesulfonate), and methanesulfonic acid (methanesulfonate). WO’261 at 28-29.
Accordingly, one having ordinary skill in the art at the time of filing would have a reasonable expectation of success in preparing, purifying, and/or handling the corresponding hydrochloride, benzenesulfonate, 4-methyl benzesulfonate, and methanesulfonate salts of the instant enantiomers 1 and 2 because
WO’261 explains that “[i]t may be convenient or desirable to prepare, purify, and/or handle a corresponding salt of the active compound,” and explains that hydrochloride, benzenesulfonate, 4-methyl benzesulfonate, and methanesulfonate salts are pharmaceutically acceptable salts, and
the instant enantiomers 1 and 2 are derived from the phthalazinone – aryl – benzofused γ-lactam scaffold of WO’261.
Therefore, claims 1 and 6 were obvious at the time of filing.
Claims 12, 18, 24, and 32 were Obvious at the Time of Filing
Claims 12, 18, 24, and 32 are generally directed to various crystalline salts of compound 1.
To the extent that these claims attempt to claim all crystalline forms of the hydrochloride (claim 12), benzenesulfonate (claim 18), 4-methyl benzesulfonate (claim 24), and methanesulfonate (claim 32) salts of compound 1, they are rejected as obvious for the same reasons claim 1 was obvious, in light of WO’261 disclosing that “[i]f the compound is in crystalline form, it may exist in a number of different polymorphic forms.” WO’261 at 26. Accordingly, one having ordinary skill in the art at the time of filing through the process of ordinary and routine optimization of the biological activity of lead compounds in drug discovery would have a reasonable expectation of success in arriving at the crystalline polymorphs of the salts of claim 1.
See supra rejection of claims 12, 18, 24, and 32 under 35 U.S.C. 112(a).
Claim 55 was Obvious at the Time of Filing
Claim 55 recites a pharmaceutical composition comprising a compound according to claim 1, and a pharmaceutically acceptable excipient.
WO’261, Peddibhotla 2009, Yu 2016, Zhu 2012, Patani 1996, and Berge 1977 are relied upon as above.
The above section regarding that compounds 1 and 2 were obvious at the time of filing, and the rejection of claim 1, is incorporated herein.
Regarding pharmaceutical compositions, WO’261 discloses that for compounds derived from the phthalazinone – aryl – benzofused γ-lactam scaffold of WO’261:
While it is possible for the active compound to be administered alone, it is preferable to present it as a pharmaceutical composition (e.g., formulation) comprising at least one active compound, as defined above, together with one or more pharmaceutically acceptable carriers, adjuvants, excipients, diluents, fillers, buffers, stabilisers, preservatives, lubricants, or other materials well known to those skilled in the art and optionally other therapeutic or prophylactic agents.
WO’261 at 55-56, and
Unless otherwise specified, a reference to a particular compound also includes ionic, salt, solvate, and protected forms of thereof, for example, as discussed below, as well as its different polymorphic forms.
WO’261 at 28 (emphasis added).
Accordingly, one having ordinary skill in the art at the time of filing would have a reasonable expectation of success in preparing a pharmaceutical composition comprising the corresponding hydrochloride, benzenesulfonate, 4-methyl benzesulfonate, and/or methanesulfonate salts of the instant enantiomer 1 and a pharmaceutically acceptable excipient, because
WO’261 explains that “[w]hile it is possible for the active compound to be administered alone, it is preferable to present it as a pharmaceutical composition (e.g., formulation) comprising at least one active compound, as defined above, together with one or more pharmaceutically acceptable … excipients…”, WO’261 at 55-56,
WO’261 explains that references to “compound” includes “salt … forms … thereof”, WO’261 at 28, and
the claimed salts of the instant enantiomers 1 are derived from the phthalazinone – aryl – benzofused γ-lactam scaffold of WO’261.
Therefore, claim 55 was obvious at the time of filing.
Claims 59, 60, 63, and 65-69 are Obvious over WO’261 in view of Peddibhotla 2009, Yu 2016, Zhu 2012, Patani 1996, Berge 1977, and the LYNPARZA® Label
Claims 59, 60, 63, and 65-69 are rejected under 35 U.S.C. 103 as being unpatentable over WO’261, in view of Peddibhotla 2009, Yu 2016, Zhu 2012, Patani 1996, Berge 1977, the LYNPARZA® Label. 19
Claim 59 depends upon claim 1 and recites a method of inhibiting a catalytic activity of a PARP enzyme present in a cell comprising contacting the cell with an effective amount of a compound according to claim 1.
Claim 60 depends upon claim 59 and specifies that the inhibition takes place in a subject suffering from a disease or disorder, and proceeds to list a number of diseases or disorders including cancer.
Claim 63 depends upon claim 1 and recites a method for the treatment of a PARP associated disease or disorder comprising administering to a subject in need thereof an effective amount of a compound according to claim 1.
Claim 65 depends upon claim 63 and recites that the PARP associated disease, disorder or condition is an immune system-related disease, a disease or disorder involving inflammation, cancer or other proliferative disease, a hepatic disease or disorder, or a renal disease or disorder.
Claim 66 additionally depends upon claim 63 and recites that the PARP associated disease, disorder or condition is selected from a list of diseases, disorders, or conditions including cancer.
Claims 67-69 additionally depend upon claim 63 and recite that the PARP associated disease, disorder or condition is selected from various list of diseases, disorders, or conditions, all of which include ovarian cancer.
WO’261, Peddibhotla 2009, Yu 2016, Zhu 2012, Patani 1996, and Berge 1977 are relied upon as above.
The above section regarding that compounds 1 and 2 were obvious at the time of filing, and the rejection of claim 1, is incorporated herein.
WO’261 discloses that PARP inhibition is useful for the treatment of cancer by preventing the ability of PARP to repair damaged DNA, which in turn causes cell death. See WO’261 1-4.
WO’261 discloses the anticancer uses for compounds derived from the phthalazinone – aryl – benzofused γ-lactam scaffold of WO’261:
A fourth aspect of the present invention relates to the use of a compound of the first aspect in the preparation of a medicament for:
(a) inhibiting the activity of PARP (PARP-1 and PARP-2) , preferably in order to maximise DNA repair inhibition;
(b) the treatment of: vascular disease; septic shock; haemorraghic shock; ischaemic injury, both cerebral and cardiovascular; reperfusion injury, both cerebral and cardiovascular neurotoxicity, including acute and chronic treatments for stroke and Parkinsons disease; inflammatory diseases, such as arthritis; multiple sclerosis; secondary effects of diabetes; as well as the acute treatment of cytotoxicity following cardiovascular surgery or diseases ameliorated by the inhibition of the activity of PARP;
(c) use as an adjunct in cancer therapy or for potentiating tumour cells for treatment with ionizing radiation or chemotherapeutic agents.
WO’261 at 20-21 (emphasis added), and
Unless otherwise specified, a reference to a particular compound also includes ionic, salt, solvate, and protected forms of thereof, for example, as discussed below, as well as its different polymorphic forms.
WO’261 at 28 (emphasis added).
WO’261 at 55 further discloses subjects for the above uses of the compounds:
The active compound or pharmaceutical composition comprising the active compound may be administered to a subject by any convenient route of administration …
The subject may be a eukaryote, an animal, a vertebrate animal, a mammal, a rodent (e.g. a guinea pig, a hamster, a rat, a mouse), murine (e.g. a mouse), canine (e.g. a dog), feline (e.g. a cat), equine (e.g. a horse), a primate, simian (e.g. a monkey or ape), a monkey (e.g. marmoset, baboon), an ape (e.g. gorilla, chimpanzee, orangutang, gibbon), or a human.
WO’261 at 55.
WO’261 at 53-54 discloses that effective amounts of an active compound derived from its scaffold can be used to inhibit the activity of PARP in a cell in vivo or in vitro:
The present invention further provides a method of inhibiting the activity of PARP in a cell, comprising contacting said cell with an effective amount of an active compound, preferably in the form of a pharmaceutically acceptable composition. Such a method may be practised in vitro or in vivo.
WO’261 at 53-54.
WO’261 at 8 discloses that effective amounts of a compound derived from its scaffold may be used in a method of treating a disease mediated by PARP
A fifth aspect of the present invention provides a method of treatment of a disease of the human or animal body mediated by PARP comprising administering to such a subject a therapeutically effective amount of a compound according to the first aspect of the invention.
WO’261 at 8.
Zhu 2012 explains the use of PARP inhibitors for the treatment of ovarian cancer:
Abrogation of the PARP-mediated DNA repair would enhance the anticancer activity of traditional cancer therapies. In addition, since tumor cells are frequently defective in DNA repair pathways like homologous recombination, inhibition of PARP-1 leads to the persistence of single-strand DNA lesions that degenerates double-strand breaks during DNA replication. Inhibition of homol-ogous recombination or PARP may be well tolerated in isolation, but combined inactivation of these distinct DNA-repair pathways results in cell death — a process called ‘‘synthetic lethality’’. There-fore PARP inhibition can be toxic to cells deficient in tumor-sup-pressor genes BRCA1 or BRCA2 that underlie high-penetrance, hereditary breast and ovarian carcinomas. Normally, homologous recombination repairs these breaks, but should this mechanism be unavailable, as is the case when BRCA1 or BRCA2 is absent, the cell dies. Thus, small-molecule inhibitors of PARP1 standalone can be an efficient targeted therapy for these cancer patients. Be-cause of the high homology between PARP-1 and PARP-2, many of the reported PARP-1 inhibitors actually inhibit PARP-2 to a sim-ilar extent. Inhibitors of PARP-1 are most likely also inhibitors of PARP2-4, so the amount of polyADP(ribosylation) is completely shut down.7 In fact, some clinical evidences have shown that drugs targeting PARP show promise as treatments for some of the most aggressive and difficult-to-treat forms of breast cancer.8
Zhu 2012 at 4635-4636 (emphasis added).
LYNPARZA® Label
AstraZeneca received FDA approval to market olaparib in 2014, which it sells as LYNPARZA® (olaparib) tablets, for oral use. See LYNPARZA® Label at 1.
LYNPARZA® is indicated for the treatment of certain aspects of ovarian, breast, pancreatic, and prostate cancer. Id.
The structure of olaparib is provided below from an excerpt of the LYNPARZA® Label:
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LYNPARZA® Label at 26.
The LYNPARZA® Label at 26 explains that olaparib is a PARP inhibitor, and provides its mechanism of action:
Olaparib is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP1, PARP2, and PARP3. PARP enzymes are involved in normal cellular functions, such as DNA transcription and DNA repair. Olaparib has been shown to inhibit growth of select tumor cell lines in vitro and decrease tumor growth in mouse xenograft models of human cancer, both as monotherapy or following platinum based chemotherapy. Increased cytotoxicity and anti-tumor activity following treatment with olaparib were noted in cell lines and mouse tumor models with deficiencies in BRCA1/2, ATM, or other genes involved in the homologous recombination repair (HRR) of DNA damage and correlated with platinum response. In vitro studies have shown that olaparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes, resulting in DNA damage and cancer cell death.
LYNPARZA® Label at 26.
Claims 59, 60, 63, and 65-69 were Obvious at the Time of Filing
One having ordinary skill in the art at the time of filing would have a reasonable expectation of success in competitively binding the PARP-1 catalytic domain with a racemic mixture of the instant enantiomers 1 and 2 for the reasons stated regarding why a racemic mixture of the instant enantiomers 1 and 2 was obvious at the time of filing. See supra discussion regarding that compounds 1 and 2 were obvious at the time of filing.
Further, one having ordinary skill in the art at the time of filing would be strongly motivated to separate the racemic mixture of the instant enantiomers 1 and 2 for the reasons stated why one of ordinary skill in the art at the time of filing through the process of ordinary and routine optimization of the biological activity of lead compounds in drug discovery would have a reasonable expectation of success in arriving at the pure instant enantiomers 1 and 2. See supra discussion regarding that compounds 1 and 2 were obvious at the time of filing.
Furthermore, one having ordinary skill in the art at the time of filing would have a reasonable expectation of success in preparing, purifying, and/or handling the corresponding hydrochloride, benzenesulfonate, 4-methyl benzesulfonate, and methanesulfonate salts of the instant enantiomer 1 for the reasons stated regarding the obviousness of claim 1.
Now, one having ordinary skill in the art at the time of filing would have a reasonable expectation of success in developing a method of competitively binding the PARP-1 catalytic domain of a PARP-1 enzyme present in a cell with a salt of the enantiomer that showed the most activity towards the catalytic domain, because
WO’261 discloses compounds derived from the phthalazinone – aryl – benzofused γ-lactam scaffold of WO’261 may be used for inhibiting the activity of PARP in subjects that have cancer, WO’261 at 20-21 and 55,
WO’261 discloses effective amounts for such methods (WO’261 at 126-7, claim 28, and WO’261 at 53-54, and 8),
WO’261 explains that references to “compound” includes “salt … forms … thereof”, WO’261 at 28, and
the claimed salts of the instant enantiomer 1 are derived from the phthalazinone – aryl – benzofused γ-lactam scaffold of WO’261.
Therefore, claims 59 and 60 were obvious at the time of filing.
Moreover, one having ordinary skill in the art at the time of filing would have a reasonable expectation of success in developing a method for the treatment of a PARP associated disease or disorder, such as ovarian cancer, comprising administering to a subject in need thereof an effective amount of a salt of the enantiomer that showed the most activity towards the PARP-1 catalytic domain because:
Zhu 2012 explains that “small-molecule inhibitors of PARP1 standalone can be an efficient targeted therapy for these cancer patients”, Zhu 2012 at 4635-4636,
Such treatment methods are exemplified by olaparib/LYNPARZA®, which is an FDA approved small-molecule PARP inhibitor bearing the same phthalazinone – aryl scaffold as the instant enantiomers, see supra excerpts from the LYNPARZA® Label,20
WO’261 discloses compounds derived from the phthalazinone – aryl – benzofused γ-lactam scaffold of WO’261 may be used for inhibiting the activity of PARP in subjects that have cancer, WO’261 at 20-21 and 55,
WO’261 discloses effective amounts for such methods (WO’261 at 126-7, claim 28, and WO’261 at 53-54, and 8),
WO’261 explains that references to “compound” includes “salt … forms … thereof”, WO’261 at 28, and
the claimed salts of the instant enantiomer 1 are derived from the phthalazinone – aryl – benzofused γ-lactam scaffold of WO’261.
Therefore, claims 63, and 65-69 were obvious at the time of filing.
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 and 6 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 26 of copending Application No. 17/996,030 (the “Reference Application”)21 in view of Berge 1977 and WO’261.
Claim 26 of the Reference Application claims 1) a racemic mixture of the instant enantiomers 1 and 2, 2) isolated enantiomers 1 and 2, and 3) pharmaceutically acceptable salts thereof. A portion of claim 26 of the Reference Application is reproduced below:
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Reference Application claim 26, received 2/12/2026.
Claim 26 of the reference application does not disclose the specific hydrochloride, 4-methylbenzenesulfonate, methanesulfonate, and benzenesulfonate salts of the instant enantiomers 1 and 2.
Berge 1977 at 2, Table 1, explains that benzenesulfonate salts are pharmaceutically acceptable salts.
WO’261 further discloses pharmaceutically acceptable salts of the PARP inhibitors may be derived from hydrochloric acid (hydrochloride), toluenesulfonic acid (4-methyl benzenesulfonate), and methanesulfonic acid (methanesulfonate). WO’261 at 28-29.
One having ordinary skill in the art at the time of filing would have a reasonable expectation of success in preparing the pharmaceutically acceptable salts claimed in the instant claims 1 and 6, because
the Reference Application discloses the genus of such salts,
WO’261 specifically discloses that for compounds derived from the phthalazinone – aryl – benzofused γ-lactam scaffold of WO’261, hydrochloride, 4-methyl benzenesulfonate, methanesulfonate salts are pharmaceutically acceptable,
WO’261 references Berge 1977, which further explains that benzesulfonate salts are pharmaceutically acceptable, and
The instant enantiomers are derived from the phthalazinone – aryl – benzofused γ-lactam scaffold of WO’261.
Accordingly, instant claims 1 and 6 are unpatentable over claim 26 of the Reference Application in view of Berge 1977 and WO’261.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
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/C.E.R./ Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/ Supervisory Patent Examiner, Art Unit 1629
1 Claims 12, 18, 24, and 32 are generally directed to hydrochloride, benzenesulfonate, mono-methylbenzene sulfonate, and methane sulfonate crystalline salts of compound 1, respectively.
2 Preparation and characterization of a single benzene sulfonate salt of compound 1 is provided in Example 1B, Specification at 39. Further see Example 1C, Specification at 39-40 (two 4-methylbenzene sulfonate salts), and Example 1D, Specification at 40-43 (four methane sulfonate salts).
3 The examiner acknowledges ipsis verbis support for other “embodiments” of hydrochloride salts appears in the Specification. See, e.g., Specification at 9, paragraph [57] (“In yet another embodiment, the hydrochloride salt (e.g., the mono-hydrochloride salt) of Compound 1 exhibits an X-ray powder diffraction (XRPD) pattern exhibiting one or more (such as 1, 2, 3, 4, 5, 6, 7 or 8) characteristic peaks at 5.32, 10.65, 14.91, 15.22, 16.68, 19.90, 21. 75, 21.99, 23.84, 25.08, 27.14 ± 0.05, 0.1, or 0.2 ° 2θ.”). However, such ipsis verbis support does not satisfy the written description requirement. See MPEP 2163.03, subsection V (“The written description requirement is not necessarily met when the claim language appears in ipsis verbis in the specification. "Even if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed. The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement."Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002).”).
4 See, e.g., Igor Ivanisevic et al., Uses of X-Ray Powder Diffraction in the Pharmaceutical Industry, in Pharmaceutical Sciences Encyclopedia: Drug Discovery, Development, and Manufacturing (Shayne C. Gad ed., 2010), hereinafter “Ivanisevic 2010” at 1.
5 See, e.g., Revision 1, “G-14 Characterization of Crystalline and Partially Crystalline Solids by X-ray Powder Diffraction (XRPD)”, USP-NF, November 2020, at 8-9 (for qualitative phase analysis by XRPD, and in certain cases “[i]t is generally sufficient to scan past the 10 strongest reflections identified in single phase XRPD database files.”).
6 See, e.g., Aurora J. Cruz-Cabeza et al., “Facts and fictions about poloymorphism”, Chem. Soc. Rev., vol. 44, pp. 8619-8635 (2015), hereinafter “Cruz-Cabeza 2015”, at 8632 (“We have found that at least one in two compounds, when screened for polymorphs, displays polymorphism. Similar statistical values were also derived for cocrystals and salts and slightly lower values were found for solvates and hydrates.”).
7 See, e.g., Instant claim 32, options (c) and (g), which recite XRPD “characteristic peaks” for different crystalline methane sulfonate salts of compound 1 that are at 5.74 and 5.73 ° 20. Given the experimental error recited in the claims, i.e., ± 0.2° 2θ, these XRPD “characteristic peaks” observed from two different crystalline methane sulfonate salts overlap.
8 Specification at 39-40.
9 Martin et al., “PHTHALAZINONE DERIVATIVES”, International Publication No. WO 03093261 A1, published November 13, 2003, hereinafter “WO’261”.
10 Satyamaheshwar Peddibhotla, “3-Substituted-3-hydroxy-2-oxindole, an Emerging New Scaffold for Drug Discovery with Potential Anti-Cancer and other Biological Activities”, Current Bioactive Compounds, vol. 5, pp. 20-38 (2009), hereinafter “Peddibhotla 2009”.
11 Bin Yu et al., “Catalytic asymmetric synthesis of biologically important3-hydroxyoxindoles: an update”, Beilstein Journal of Organic Chemistry, vol. 12, pp. 1000-1039 (2016), hereinafter “Yu 2016”.
12 Zhu, Gui-Dong, et al. "Discovery and SAR of orally efficacious tetrahydropyridopyridazinone PARP inhibitors for the treatment of cancer", Bioorganic & medicinal chemistry, vol. 20, no. 15, pp. 4635-4645 (2012), hereinafter “Zhu 2012”.
13 George A. Patani and Edmond J. LaVoie, “Bioisosterism: A Rational Approach in Drug Design”, Chem. Rev., vol. 96, no. 8, pp. 3147-3176 (1996), hereinafter “Patani 1996”.
14 Berge et al., "Pharmaceutically Acceptable Salts", J. Pharm. Sci., vol. 66, no. 1, pp. 1-19 (1977), hereinafter “Berge 1977”.
15 Also included in the Figure is the Example 8 compound of WO’261 at 70-71 (showing the analogous phthalimide moiety of the above oxisoindole/phthalimidine), which has a mammalian PARP IC50 of less than 0.30 μM. WO’261 at 119.
16 Peddibholta 2009 includes 3,3’-spirocycle derivatives of the scaffold which show similar structure and activity.
17 As discussed supra, the Example 1 compound also inhibits mammalian PARP with an IC50 of less than 0.30 μM. WO’261 at 119.
18 See also, Patani 1996 at 3148 (explaining that “[t]he critical component for bio-isosterism is that bioisosteres affect the same phar-macological target as agonists or antagonists and, thereby, have biological properties which are related to each other.”) (emphasis added).
19 LYNPARZA® Label, revised 3/2021, hereinafter the “LYNPARZA® Label”.
20 The examiner acknowledges that the central aryl groups of olaparib and the instant enantiomers are considered equivalent bioisosteres. See supra discussion of Patani 1996.
21 Published as U.S. Patent Application Publication No. 20230234938 A1, Assigned to RHIZEN PHARMACEUTICALS AG.
Prosecution Insights