Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
This Application claims domestic benefit of U.S. Provisional Application No. 63/306,781, filed Feb. 4, 2022, and is a 371 of PCT/US2023/012252, filed Feb. 3, 2023.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on Sept. 19, 2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Status
Claims 1-2, 6, 10, 17, 31, 35, 43, 50, 54, 66, 81, 89, 103, 117, 124, 131, 138, 145, 152, 163, 174, 181, 188, and 194 are currently pending and subject to examination.
Specification
The disclosure is objected to because of the following informalities: In example 21, the succinate salt form is purported to be formed by reaction with “lactic acid” instead of succinic acid.
Appropriate correction is required.
Claim Rejections – 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
“(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.”
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
“The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.”
Claims 1 and 194 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.
One of ordinary skill in the art cannot determine the metes and bounds of the claimed invention because the preamble of claim 1 recites “a crystalline form of AMG 397” which appears to be a limitation because it implies a specific structure to the form of AMG 397 (See MPEP § 2111.03(I) (“Any terminology in the preamble that limits the structure of the claimed invention must be treated as a claim limitation.”). The body of the claim, however, recites “an amorphous form of AMG 397” which is not a crystalline form, leading to confusion over the intended scope of the claim. Claim 194 depends from claim 1 and does not resolve this ambiguity and is therefore also indefinite.
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 1-2, 6, 10, 17, 31, 35, 43, 50, 54, 66, 81, 89, 103, 117, 124, 131, 138, 145, 152, 163, 174, 181, 188, and 194 fail to comply with the written description requirement:
Claims 1-2, 6, 10, 17, 31, 35, 43, 50, 54, 66, 81, 89, 103, 117, 124, 131, 138, 145, 152, 163, 174, 181, 188, and 194 are rejected under 35 U.S.C. § 112, first paragraph, as failing to comply with the written description requirement. The claims 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 inventors, at the time the application was filed, had possession of the claimed invention.
The written description requirement is distinct from the enablement requirement; as was first pointed out by the court in In re Ruschig, 3 79 F .2d 990, 154 USPQ 118 (CCP A 1967), and clarified in Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 19 USPQ2d 1111 (Fed. Cir. 1991). The issue of whether the claimed subject matter is adequately supported/described by the specification, is a question of fact. Id. at 1563, 19 USPQ2d at 1116.
When considering whether the claimed subject matter complies with the written description requirement, Applicants' disclosure should be read in light of the knowledge possessed by those skilled in the art.
"[T]he disclosure in question must be read in light of the knowledge possessed by those skilled in the art, and that knowledge can be established by affidavits of fact composed by an expert, and by referencing to patents and publications available to the public ... "
In re Lange, 644 F.2d 856, 863, 209 USPQ 288, 294. See also, In re Alton, 76 F.3d 1168, 37 USPQ2d 1578 (Fed. Cir. 1996).
Applicants enjoy the presumption that their patent application is valid and all statements contained therein are accurate; it is the PTO's burden to demonstrate why any of Applicants claims should be rejected or why any of Applicant's statements should be doubted.
"it is incumbent upon the Patent Office, whenever a rejection ... is made, to explain why it doubts the truth or accuracy of any statement in a supporting disclosure and to back up assertions of its own with acceptable evidence or reasoning which is inconsistent with the contested statement. Otherwise, there would be no need for the applicant to go to the trouble and expense of supporting his presumptively accurate disclosure."
In re Marzocchi, 439 F.2d 220, 224, 169 USPQ 367, 370. If successful in presenting such evidence and argument, the burden then shifts to the Applicant to provide evidence that would convince one to the contrary.
The Invention in General
A component of Applicant’s invention is directed to crystal forms of a compound, AMG 397, having the structure:
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(Spec., ¶ [0002]) (herein “the compound” ).
The compound is described as an inhibitor of Mcl-1 which are regarded as potentially useful for the clinical treatment of cancers (background). The application discloses numerous solid forms of the compound including polymorphs, solvates and amorphous forms, distinguished, and characterized principally on the basis of nuclear magnetic resonance (NMR), x-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and thermal gravimetric analysis (TGA).
The Claimed Invention
The claimed invention is directed to crystalline forms of the compound (claims 1-2, 6, 10, 17, 31, 35, 43, 50, 54, 66, 81, 89, 103, 117, 124, 131, 138, 145, 152, 163, 174, 181, 188) and a method of treating a subject suffering from cancer comprising administering to the subject a therapeutically effective amount of the crystal form of claim 1. The independent claims characterize the crystal forms primarily by three XRPD peaks. The dependent claims require either additional peaks characterizing the form or thermogravimetric analysis (TGA) or differential scanning calorimetry (DSC) data.
The Supporting Disclosure
Applicants' supporting disclosure describes the chemical formula and structure of the compound (p. 1-2). The drawings of the disclosure provide, inter alia, powder x-ray diffraction patterns, DSC curves, and TGA curves for the various crystal forms. Peaks of interest from the diffraction patterns are provided in the tables. For example, the disclosure identifies dozens x-ray diffraction peak positions characteristic of the crystal form (Table 1).
The disclosure also provides two example methods preparing the crystal form (Examples 1-31), from a sample of the compound of unspecified solid form. Example 1 involves charging AMG 397 with a solution of L-arginine (1:1) in trifluoroethanol to form a solution, stirring for three days at room temperature and isolating the resulting solid (Example 1; ¶ [00272]).
The State of the Art
A number of references establish that different polymorphs, or crystal forms, of the same compound may often have shared or highly similar XRD peaks, Raman peaks, and solid-state NMR peaks. These references further establish that, because of such peak overlap and similarity, a minimum number of peaks is required in order to definitively characterize a single polymorph and distinguish it from all others that may exist, including any that are known and any that have yet to be discovered.
For example, the non-patent publication, “Thermoanalytical and Crystallographic Methods.” Polymorphism in Pharmaceutical Solids, 2nd edition, Editor Brittain, Publ. Informa Healthcare USA, pgs. 318-346 (2009) by Bhattacharya et al. (hereinafter, “Bhattacharya”), states that
The United States Pharmacopeia contains a general chapter on XRD, which sets the criterion that identity is established if the scattering angles in the powder patterns of the sample and reference standard agree to within the calibrated precision of the diffractometer. It is noted that it is generally sufficient that the scattering angles of the ten strongest reflections obtained for an analyte agree to within either ± 0.10 or ± 0.20° 2 q , whichever is more appropriate for the diffractometer used.
-Bhattacharya, pg. 334, second full paragraph, (emphasis added)
As such, Bhattacharya teaches ten XRD peaks is a standard for identifying a polymorph and distinguishing it from other polymorphs. Bhattacharya notes that in select circumstances, as few as five XRD peaks have been utilized for polymorph identification (pg. 334, last paragraph), but ten is described as the standard, and no example is suggested in which a number of XRD peaks as few as three has been deemed sufficient to identify a solid polymorph and distinguish the polymorph from other forms of the same substance.
Bhattacharya also teaches that DSC profiles can be used to distinguish polymorphs, but shows that two different polymorphs can have peaks within about 10°C of each other. Figure 1 shows that Form III has a DSC peak at about 167-168°C while form II has a DSC peak at about 173°C :
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Bhattacharya, Fig. 1, p. 320.
Bhattacharya also teaches that thermogravimetric (TG) analysis can be used to aid in the identification and characterization of solvatomorphs but is typically not used alone to identify pure polymorphs (Bhattacharya, p. 324-325).
An additional publication, “Preparation and Identification of Polymorphs and Solvatomorphs” by Harry G. Brittain (CRC Press, 2008, p. 185-228) (herein “Brittain”) explains that different polymorphs of than same compound can be obtained using different solvents or even highly similar solvents. For example:
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Brittain, p. 206.
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Brittain, p. 208.
Brittain teaches that the polymorphic form is also dependent on temperature. For example:
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Brittain, p. 214.
Summary of Written Description Rejection
In view of the findings described above, and assuming the presently disclosed peaks accurately and consistently characterize the species to which they are assigned, the only effect of claiming one of the presently disclosed polymorphs, while reciting a small number of identifying peaks (3), would be to broaden the claim in a manner that allows it to potentially encompass polymorphic species not disclosed and perhaps not yet discovered. However, because only one specific polymorph of the compound is disclosed, and in order to comply with the written description requirement, the claims should be sufficiently specific and detailed to encompass only the polymorph that is disclosed and to exclude any non-disclosed polymorphs, such as any polymorphs that are yet to be discovered.
While the Applicant also recites a mass reduction rates and a DSC peaks in the dependent claims, these limitations do not serve to fully identify the claimed polymorph because TGA analysis can only aid in the identification of polymorphs, is typically used in conjunction with other identification techniques, and is more useful in distinguishing solvatomorphs, and the range for the DSC peak is so broad that it does not exclude other polymorphs.
For the aforementioned reasons, claims 1-2, 6, 10, 17, 31, 35, 43, 50, 54, 66, 81, 89, 103, 117, 124, 131, 138, 145, 152, 163, 174, 181, 188, and 194 fail to comply with the written description requirement.
Claims 1, 35, 50, and 194 fail to comply with the enablement requirement.
Claims 1, 35, 50, and 194 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the solid forms recited in claims 2, 6, 10, 17, 31, 43, 54, 66, 89, 103, 117, 131, 138, 145, 152, 163, 171, 181 and 188, does not reasonably provide enablement for the crystalline acetic acid solvate or the amorphous sodium salt. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make the invention commensurate in scope with these claims. Claim 194 is rejected to the extent that it depends on claim 1.
In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is “reasonable” or is “undue.” Consistent with Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Wands factors continue to provide a framework for assessing enablement in a utility application or patent, regardless of technology area. See Guidelines for Assessing Enablement in Utility Applications and Patents in View of the Supreme Court Decision in Amgen Inc. et al. v. Sanofi et al., 89 FR 1563 (January 10, 2024). These factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988) (reversing the PTO’s determination that claims directed to methods for detection of hepatitis B surface antigens did not satisfy the enablement requirement). In Wands, the court noted that there was no disagreement as to the facts, but merely a disagreement as to the interpretation of the data and the conclusion to be made from the facts. In re Wands, 858 F.2d at 736-40, 8 USPQ2d at 1403-07. The court held that the specification was enabling with respect to the claims at issue and found that “there was considerable direction and guidance” in the specification; there was “a high level of skill in the art at the time the application was filed;” and “all of the methods needed to practice the invention were well known.” 858 F.2d at 740, 8 USPQ2d at 1406. After considering all the factors related to the enablement issue, the court concluded that “it would not require undue experimentation to obtain antibodies needed to practice the claimed invention.” Id., 8 USPQ2d at 1407.
(A) The breadth of the claims. Each rejected claim is drawn to a product defined by its physical characteristics and is unlimited as to the process by which the form is obtained. Enablement must therefore be commensurate with the full scope of the product claimed.
(B) The nature of the invention and (E) the level of predictability in the art. Each rejected claim is drawn to a specific solid form of a structurally complex active pharmaceutical ingredient (AMG 397), defined by ARPD, DSC, or solid state NMR characteristics. Which solid phase crystallizes from a given system is an empirical outcome governed by crystallization and aging temperature, supersaturation, solvent and antisolvent ratio, water activity, seeding, aging time, and drying conditions. Solid form selection is recognized as an unpredictable art because it is difficult to predict how a molecule will pack into a crystal lattice under different conditions and the characteristics that a solid form will have (see Brittain, p. 185-191 (explaining how extensive experiments are necessary to characterize the polymorphs of a substance and how these solid forms have different and unpredictable properties)).
(F) The amount of direction or guidance presented and (G) the existence of working examples. It is acknowledged that the specification recites operative conditions for the majority of the disclosed forms. See, e.g., [00276] (Example 2: charging AMG 397 with a solution of L-arginine (1:1) in hexafluoroisopropanol, stirring for 2 days at room temperature to form a suspension). The rejected claims are distinguished from these forms by the absence of any comparable guidance.
For the acetic acid solvate, the sole disclosure is Example 7 at ¶ [00301], reproduced below:
Cystalline AMG 397 Acetic Acid solvate was formed as follows. AMG 397 is combined with ethanol and aqueous sodium hydroxide. Aqueous acetic acid is added and the resulting slurry aged. The product is collected by filtration. The isolated solids were AMG 397 acetic acid solvate, which was characterized as shown in the below tables.
No quantity, concentration, or equivalents of any reagent is recited, neither is any crystallization temperature, aging time, colling profile, seeding or drying conditions.
For the amorphous sodium salt form, the sole disclosure is Example 9 at ¶ [00309]
AMG 397 amorphous sodium salt form 1 was formed by extracting AMG 397 from 100 mg drug product tablet using Me-THF and solvent exchange to ethanol, then adding NaOH to form the sodium salt. The wet-cake was vacuum-dried under N2 flow to yield the sodium salt.
No stoichiometry, temperature, time, or concentration is recited at any step. Independently, the starting material is a formulated drug product whose composition, excipients, and source are nowhere disclosed in the specification. A person of ordinary skill in the art would not know the identity of the required input. Other examples in the specification recite the operative conditions for the forms that they describe.
(C) The state of the prior art. Tom et al. (Organic Research Process & Development, 2021, 25(3), 486-499) (of record, IDS NPL cite no. 3) (“Tom”) describes the crystallization of AMG 397 from the same solvent system of Example 7 in the instant specification, as well as the sodium salt form of the compound in crystalline form:
The original isolation process started with a heptane/2-methyltetrahydrofuran technical-grade crystallization followed by an aqueous acetic acid/ethanol form-setting recrystallization to provide the desired form of the API. During development, alternative solvent systems were investigated, but the low solubility of the free-form API in most solvents limited the selection. The acyl sulfonamide functionality in the API is in the sodium salt form after workup, so aqueous acetic acid was used in the crystallization to adjust the pH and isolate the free-form of the API. (35) Solubility studies demonstrated that 2–3 equiv of acetic acid was optimal to minimize mother liquor losses and effectively reject impurities (Figure 10). Adding aqueous acetic acid to the solution of the API in denatured ethanol over 1 h at 80 ± 5 °C resulted in an effective crystallization that provided API 2 with >98% purity in >75% yield with minimal losses (Figure S3).
Tom, p. 494, col. 2;
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Id., scheme 3.
Tom however, does not obtain an acetic acid solvate, but rather a zwitterion and variable hydrate (endnote 35).
Tom further establishes that the solid form obtained from this solvent system is controlled by the very parameters that the specification omits:
The concentrated solution was polish-filtered. To the filtered solution was charged 5 N NaOH (51 mL) followed by 13 wt % NaCl solution (206 mL). The solution was agitated for at least 5 min at 20 °C. The agitation was stopped, and the phases were allowed to separate for at least 5 min at 20 °C. The aqueous layer was removed. Additional 13 wt % NaCl solution (206 mL) was charged to the organic layer, and the batch was agitated for at least 5 min at 20 °C. The agitation was stopped, and the phases were allowed to separate for at least 5 min at 20 °C. The aqueous layer was removed. Denatured ethanol with 2% v/v toluene (946 mL) was charged to the organic layer. The batch was distilled to about 0.13 M at 50 °C under vacuum. Denatured ethanol with 2% v/v toluene (997 mL) was charged to the distilled solution, and the batch was distilled to about 0.13 M at 50 °C under vacuum. Another portion of denatured ethanol with 2% v/v toluene (997 mL) was charged to the distilled solution, and the distillation was repeated once more. The batch was polish-filtered and then heated to 80 ± 5 °C. After this temperature was reached, 3 N AcOH (22 mL, 0.14 mol, 0.5 equiv) was charged to the heated solution. The solution was aged at 80 ± 5 °C for at least 15 min. In a separate vessel, a slurry of AMG 397 2 seed (0.51 g) in denatured ethanol with 2% v/v toluene (2.6 mL) was prepared. The seed slurry was then charged to the heated solution. The solution was aged for at least 15 min at 80 ± 5 °C. A 3 N solution of AcOH (108 mL, 0.70 mol, 2.5 equiv) was then charged over a period of 1 h at 80 °C, and then the batch was slowly cooled to 20 °C over a period of 1 h. The slurry was aged at 20 °C for at least an additional 1 h, followed by filtration of the solid. The cake was washed with denatured ethanol with 2% v/v toluene (2 × 308 mL). The filtered solids were dried at 65 °C under vacuum for at least 12 h to obtain AMG 397(75.6 g, 96.1 wt %, 76% yield).
Tom, p. 496-97.
Tom additionally reports solubility studies establishing that 2-3 equivalents of acetic acid was optimal (show above p. 494), confirming that acid stoichiometry was itself an experimentally determined variable.
(D) The level of skill of those of ordinary skill in the art. The level of skill in the art is high, encompassing an advanced degree in chemistry or a related discipline together with experience in solid state form screen. A high level of skill does not, however, supply the operative conditions that are absent from the disclosure and that the prior art shows to be outcome determinative.
(H) Quantity of Experimentation Necessary. Considering the foregoing, a person of ordinary skill seeking to make the acetic acid solvate or the sodium salt amorphous forms would be required to undertake an extended open-ended screening campaign across reagent equivalents, concentration, water content, crystallization and aging temperature, seeding, cooling or evaporation rate, and drying conditions, with no disclosed starting point. With respect to the acetic acid solvate, there is affirmative evidence that the most fully characterized conditions in the disclosed solvent system deliver a different solid form. With respect to the amorphous sodium salt, the starting material itself is undisclosed and the sodium salt is known to crystallize. Such a program is not routine optimization of disclosed conditions but independent research to discover the conditions that the specification never provides.
Accordingly, one of ordinary skill in the art would be required to engage in undue experimentation to make the acetic acid and sodium salt amorphous forms of claims 1, 35 and 50, together with claim 194 as it depends therefrom, and these claims are not enabled by the disclosure.
Claim Rejections – 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
“A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.”
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claim(s) 1 and 132 is/are rejected under 35 U.S.C. 103 as being unpatentable over Tom et al. (Organic Research Process & Development, 2021, 25(3), 486-499) (of record, IDS NPL cite no. 3) in view of Harrington et al. (WO2018183418A1) (of record, IDS foreign document no. 1).
Claim 1 is directed towards a crystalline form of AMG 397: (xiv) as a phosphate salt, characterized by 13C NMR peaks at 5.8, 15.0, 18.3, 21.2, 22.2, 23.6, 27.6, 27.6, 29.3, 31.7, 31.9, 35.7, 41.3, 43.6, 49.9, 51.7, 53.3, 53.7, 55.8, 57.7, 58.8. 58.9, 59.8, 61.0, 79.6, 80.9, 115.4, 117.3, 119.1, 126.0, 127.9, 128.7, 129.4, 129.5, 130.2, 139.2, 139.8, 139.9, 150.8, and 168.8 ± 0.5 ppm.
Tom discloses a crystalline forms of AMG 397 as salts and free bases, wherein the crystalline form of the free base is characterized by 13C NMR peaks substantially identical to those which are claimed for the phosphate salt:
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Tom, p. 487, scheme 1;
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Tom, p. 497, col. 1.
While Tom does not teach the phosphate salt of AMG 397, one of ordinary skill in the art would have a reasonable expectation of success to obtain the phosphate salt of AMG 397 because pharmaceutically acceptable salts of AMG 397 are commonly known in the art and readily obtained by conventional methods.
For example, Harrington teaches AMG 397 and pharmaceutically acceptable salts thereof, including phosphate salts:
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Harrigton, Spec., p. 283; example 10;
The compounds of the present invention can be administered as pharmaceutically acceptable salts, esters, amides or prodrugs. The term "salts" refers to inorganic and organic salts of compounds of the present invention. The salts can be prepared in situ during the final isolation and purification of a compound, or by separately reacting a purified compound in its free base or acid form with a suitable organic or inorganic base or acid and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, palmitiate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like.
Id., p. 247, ll. 7-17 (emphasis added).
Therefore, claim 1 was prima facie obvious at the time of filing.
Claim 182 is directed towards a method of treating a subject suffering from cancer, comprising administering to the subject a therapeutically effective amount of the crystalline form of claim 1. One of ordinary skill in the art would have a reasonable expectation of success to treat a subject suffering from cancer, comprising administering to the subject a therapeutically effective amount of the crystalline form of claim 1, because AMG 397 is known in the art as an anti-cancer therapeutic. For example, Tom teaches that AMG 397 is a small molecule Mcl-1 inhibitor for the treatment of multiple myeloma and acute myeloid leukemia (Tom, p. 486, col. 1). Moreover, Harrigton teaches a method of treating cancer including “administering to a patient in need thereof a therapeutically effective amount of the compound of any of the embodiments or a pharmaceutically acceptable salt thereof.” (Harrington, Spec., p. 14, ll. 4-6). Thus, claim 182 was prima facie obvious at the time of filing.
Nonstatutory 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.
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Claims 1 and 132 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 20 of U.S. Patent No. 10,300,075 B2 (the ‘075 patent) in view of Tom et al. (Organic Research Process & Development, 2021, 25(3), 486-499) (of record, IDS NPL cite no. 3) and Harrington et al. (WO2018183418A1) (of record, IDS foreign document no. 1).
Claim 1 is directed towards a crystalline form of AMG 397: (xiv) as a phosphate salt, characterized by 13C NMR peaks at 5.8, 15.0, 18.3, 21.2, 22.2, 23.6, 27.6, 27.6, 29.3, 31.7, 31.9, 35.7, 41.3, 43.6, 49.9, 51.7, 53.3, 53.7, 55.8, 57.7, 58.8. 58.9, 59.8, 61.0, 79.6, 80.9, 115.4, 117.3, 119.1, 126.0, 127.9, 128.7, 129.4, 129.5, 130.2, 139.2, 139.8, 139.9, 150.8, and 168.8 ± 0.5 ppm.
Claims 1 and 20 of the ‘075 patent are directed towards the compound AMG 397 having the structure:
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‘075 patent, claims 1 and 20.
While the ‘075 patent does not claim crystalline forms of AMG 397, Tom discloses a crystalline forms of AMG 397 as salts and free bases, wherein the crystalline form of the free base is characterized by 13C NMR peaks substantially identical to those which are claimed for the phosphate salt:
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Tom, p. 487, scheme 1;
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Tom, p. 497, col. 1.
While Tom does not teach the phosphate salt of AMG 397, one of ordinary skill in the art would have a reasonable expectation of success to obtain the phosphate salt of AMG 397 because pharmaceutically acceptable salts of AMG 397 are commonly known in the art and readily obtained by conventional methods.
For example, Harrington teaches AMG 397 and pharmaceutically acceptable salts thereof, including phosphate salts:
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Harrigton, Spec., p. 283; example 10;
The compounds of the present invention can be administered as pharmaceutically acceptable salts, esters, amides or prodrugs. The term "salts" refers to inorganic and organic salts of compounds of the present invention. The salts can be prepared in situ during the final isolation and purification of a compound, or by separately reacting a purified compound in its free base or acid form with a suitable organic or inorganic base or acid and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, palmitiate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like.
Id., p. 247, ll. 7-17 (emphasis added).
Therefore, claim 1 is rejected on the ground of obviousness type double patenting.
Claim 182 is directed towards a method of treating a subject suffering from cancer, comprising administering to the subject a therapeutically effective amount of the crystalline form of claim 1. While the ‘075 patent does not claim a method of treating a subject suffering from cancer, one of ordinary skill in the art would have a reasonable expectation of success to treat a subject suffering from cancer, comprising administering to the subject a therapeutically effective amount of the crystalline form of claim 1, because AMG 397 is known in the art as an anti-cancer therapeutic. For example, Tom teaches that AMG 397 is a small molecule Mcl-1 inhibitor for the treatment of multiple myeloma and acute myeloid leukemia (Tom, p. 486, col. 1). Moreover, Harrigton teaches a method of treating cancer including “administering to a patient in need thereof a therapeutically effective amount of the compound of any of the embodiments or a pharmaceutically acceptable salt thereof.” (Harrington, Spec., p. 14, ll. 4-6). Therefore, claim 182 is rejected on the ground of obviousness type double patenting.
Claims 1 and 182 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 27-28 of U.S. Patent No. 10,500,213 B2 (the ‘213 patent) in view of Tom et al. (Organic Research Process & Development, 2021, 25(3), 486-499) (of record, IDS NPL cite no. 3) and Harrington et al. (WO2018183418A1) (of record, IDS foreign document no. 1).
Claim 1 is directed towards a crystalline form of AMG 397: (xiv) as a phosphate salt, characterized by 13C NMR peaks at 5.8, 15.0, 18.3, 21.2, 22.2, 23.6, 27.6, 27.6, 29.3, 31.7, 31.9, 35.7, 41.3, 43.6, 49.9, 51.7, 53.3, 53.7, 55.8, 57.7, 58.8. 58.9, 59.8, 61.0, 79.6, 80.9, 115.4, 117.3, 119.1, 126.0, 127.9, 128.7, 129.4, 129.5, 130.2, 139.2, 139.8, 139.9, 150.8, and 168.8 ± 0.5 ppm.
Claims 1 and 27-28 of the ‘213 patent are directed towards a method of a method of treating cancer (claims 1 and 27), specifically multiple myeloma, acute myelogenous leukemia, or non-Hodgkin’s lymphoma (claim 28), comprising administering to a patient in need thereof AMG 397 having the structure:
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‘213 patent, claims 1 and 27.
The rejection of claim 1 over the claims of the ‘075 patent in view of Tom and Harrington is incorporated herein by reference, to address the obviousness of the salt form recited in instant claim 1. As such claim 1 is rejected on the ground of obviousness type double patenting over the claims of the ‘213 patent.
Claim 182 is directed towards a method of treating a subject suffering from cancer, comprising administering to the subject a therapeutically effective amount of the crystalline form of claim 1. As shown in the rejection of claim 1 over the ‘213 patent, the ‘213 patent teaches a method of treating cancer comprising administering the compound of claim 1. One of ordinary skill in the art would have a reasonable expectation of success to administer the crystalline form of claim 1 given the teachings of Tom and Harrington recited above in the rejection of claims 1 and 182 over the claims of the ‘075 patent. Thus, claim 182 is rejected on the grounds of nonstatutory double patenting.
Claims 1 and 182 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 42-66 of copending Application No. 19/763,556 in view of Tom et al. (Organic Research Process & Development, 2021, 25(3), 486-499) (of record, IDS NPL cite no. 3) and Harrington et al. (WO2018183418A1) (of record, IDS foreign document no. 1).
Claim 1 is directed towards a crystalline form of AMG 397: (xiv) as a phosphate salt, characterized by 13C NMR peaks at 5.8, 15.0, 18.3, 21.2, 22.2, 23.6, 27.6, 27.6, 29.3, 31.7, 31.9, 35.7, 41.3, 43.6, 49.9, 51.7, 53.3, 53.7, 55.8, 57.7, 58.8. 58.9, 59.8, 61.0, 79.6, 80.9, 115.4, 117.3, 119.1, 126.0, 127.9, 128.7, 129.4, 129.5, 130.2, 139.2, 139.8, 139.9, 150.8, and 168.8 ± 0.5 ppm.
The claims of the copending application No. 19/763,556 are directed towards a crystalline hydrate form of AMG 397 (compound A). While the crystalline hydrate form is not identical to the crystalline form as instantly claimed, Tom discloses a crystalline forms of AMG 397 as salts and free bases, wherein the crystalline form of the free base is characterized by 13C NMR peaks substantially identical to those which are claimed for the phosphate salt and Harrison teaches the phosphate salt of the compound, as shown above. The rejection of claim 1 over the claims of the ’075 patent in view of Tom and Harrington is incorporated herein by reference. Therefore, claim 1 is provisionally rejected over the claims of the copending Application No. 19/763,556.
Claim 182 is directed towards a method of treating a subject suffering from cancer, comprising administering to the subject a therapeutically effective amount of the crystalline form of claim 1. Copending Application No. 19/763,556 claims a method of treating cancer comprising administering a pharmaceutical composition comprising the crystalline hydrate form of compound A (AMG 397) (claims 65-66). One of ordinary skill in the art would have a reasonable expectation of success to administer the crystalline form of claim 1 given the teachings of Tom and Harrington recited above in the rejection of claims 1 and 182 over the claims of the ‘075 patent. Thus, claim 182 is provisionally rejected on the grounds of nonstatutory double patenting.
This is a provisional nonstatutory double patenting rejection.
Claims 1 and 182 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 10, 18, 26, 34, 41, 48, 56, 63, 69-71 of copending Application No. 18/730,357 in view of Tom et al. (Organic Research Process & Development, 2021, 25(3), 486-499) (of record, IDS NPL cite no. 3) and Harrington et al. (WO2018183418A1) (of record, IDS foreign document no. 1).
Claim 1 is directed towards a crystalline form of AMG 397: (xiv) as a phosphate salt, characterized by 13C NMR peaks at 5.8, 15.0, 18.3, 21.2, 22.2, 23.6, 27.6, 27.6, 29.3, 31.7, 31.9, 35.7, 41.3, 43.6, 49.9, 51.7, 53.3, 53.7, 55.8, 57.7, 58.8. 58.9, 59.8, 61.0, 79.6, 80.9, 115.4, 117.3, 119.1, 126.0, 127.9, 128.7, 129.4, 129.5, 130.2, 139.2, 139.8, 139.9, 150.8, and 168.8 ± 0.5 ppm.
The claims of copending Application No. 18/730,357 are directed towards different crystalline forms of AMG 397. While the crystalline forms are not identical to the crystalline form as instantly claimed, Tom discloses a crystalline forms of AMG 397 as salts and free bases, wherein the crystalline form of the free base is characterized by 13C NMR peaks substantially identical to those which are claimed for the phosphate salt and Harrison teaches the phosphate salt of the compound, as shown above. The rejection of claim 1 over the claims of the ’075 patent in view of Tom and Harrington is incorporated herein by reference. Therefore, claim 1 is provisionally rejected over the claims of the copending Application No. 18/730,357.
Claim 182 is directed towards a method of treating a subject suffering from cancer, comprising administering to the subject a therapeutically effective amount of the crystalline form of claim 1. Copending Application No. 18/730,357 claims a method of treating cancer comprising administering a pharmaceutical composition comprising a crystalline form of AMG 397 (claims 70-71(=). One of ordinary skill in the art would have a reasonable expectation of success to administer the crystalline form of claim 1 given the teachings of Tom and Harrington recited above in the rejection of claims 1 and 182 over the claims of the ‘075 patent. Thus, claim 182 is provisionally rejected on the grounds of nonstatutory double patenting.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claim is found to be allowable.
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/HEATHER DAHLIN/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
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