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 .
DETAILED ACTION
Claim Status
Claims 2 and 18-21 were pending as of the last Office Action.
Upon amendment entry, Claims 1 and 3-17, 20-21 are cancelled.
Upon amendment entry, Claims 22-37 are added.
Claims 2, 18-19 and 22-37 are pending investigation.
Priority Status
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No foreign priority was claimed in the Instant Application; EFD is 09/18/2019.
Information Disclosure Statement
All references have been considered in the one (1) IDS(s) filed 02/02/2026 unless marked with a strikethrough.
Review of Election of Species
Species Election Requirement dated 06/18/2025: Applicant elected Group I; further elected the species: HPMCAS – hydroxypropyl methylcellulose acetate succinate as the polymer matrix; HPMC – hydroxypropyl methylcellulose as the release-controlling polymer. HPMCAS – hydroxypropyl methylcellulose acetate succinate as the crystallization inhibitor.
Examiner Responses to Arguments/Amendments
The issues raised in the prior Office Action, are addressed below:
I. Claim Amendments –
Independent Claim 2 was amended to the following:
“An oral dosage form for extended release of 6-(cyclopropaneamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (BMS-986165), the oral dosage form comprising:
(i) an internal phase comprising a spray-dried dispersion of BMS-986165 in a polymer matrix,
wherein the polymer matrix comprises one or more of: hydroxypropyl methylcellulose (HPMC), hypromellose phthalate (HPMC-P), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and Eudragit100-55; and
(ii) an external phase comprising a release-controlling polymer,
wherein the release- controlling polymer is selected from methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethylcellulose, sodium carboxymethylcellulose, ethyl cellulose, sodium alginate, chitosan, gelatin, tragacanth, xanthan, and mixtures thereof.”
II. Claim Rejections –
The 35 USC § 103 rejections were withdrawn because Applicant amended independent Claim 2, with the addition of a further limitation, as seen above.
This further limitation added though has brought forth 35 USC § 112 issues. Thus, this necessitates a new rejection below.
III. Response to Claim Rejections –
35 USC §103 Rejections
Applicant' s arguments, filed 02/02/2026, with respect to the claims have been fully considered but they are not persuasive for the following reason(s):
Applicant argues:
First, the cited art provides no motivation to pursue an extended-release dosage form of BMS-986165 in the first instance. Although Papp discloses oral administration of BMS-986165, it does not disclose any release profile or characteristics of the dosage form used in its study.
This disclosure in Papp does not describe the release characteristics of the capsules, and for at least that reason it is incorrect to say that Papp discloses an extended-release dosage form of BMS- 986165 or to say that Papp discloses any "time-release capabilities" of the capsules used in the study.
Furthermore, nothing in Papp would have suggested that extended release of BMS-986165 would offer any benefit. Papp discloses two patient groups that received the same total daily dose of 12 mg: one group receiving 12 mg once daily, and the other group receiving 6 mg twice daily.
However, Papp does not disclose or suggest that any clinical benefit or improvement would be achieved by extending the delivery of the total daily dose of 12 mg. Papp discloses that the group receiving 12 mg once daily performed at least as well as, and in most instances better than, the group receiving 6 mg twice daily, indicating that spreading the 12 mg dose into two doses over time did not confer any improved clinical outcome. The results disclosed in Papp cannot properly be said to teach any perceived advantage of modified delivery.
Accordingly, nothing in the Papp publication (whether considered alone or in combination with the other cited art) would have suggested to the person of ordinary skill in the art that the specific compound BMS-986165 should be formulated as an extended-release dosage form in the first instance.
In response to Applicant’s overall arguments that: the combination of references would not have suggested to the person of ordinary skill in the art that the specific compound BMS-986165 should be formulated as an extended-release dosage form.
Examiner disagrees for the following reasons: In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In addition to applicant' s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
In this case, Papp teaches BMS-986165 is a potent, oral TYK2 inhibitor that binds to the pseudo-kinase domain of the enzyme and is functionally more selective than other tyrosine kinase inhibitors (Papp, pg. 1314, col.1, full para 2). This is the same inhibitor that is used in the Instant Application. As such, the functional language is met for the claims. Also, a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
In the weight of this evidence, Examiner still states it is obvious with this combination of references used; the Applicant’s arguments are not persuasive.
In response to Applicant’s overall arguments that:
Even if such motivation existed, the cited art does not disclose or suggest the specific dosage form recited in the claims-namely, a dosage form comprising (among other things) a spray-dried dispersion of BMS-986165 in a polymer matrix, and an external phase comprising a release-controlling polymer.
Papp does not disclose any details of the capsules and there is nothing in Papp to suggest that the compound BMS-986165 requires or would benefit from any special formulation approaches, let alone the specific formulation of a dispersion in a polymer matrix.
In fact, bioavailability and stability challenges for the specific compound BMS-986165 are disclosed only in the present application (see, e.g., page 7, line 28 - page 8, line 7, and page 3, line 18 - page 4, line 7 of the specification as originally filed), not in the cited art.
Papp does not disclose or suggest any such challenges, and the other cited art does not concern BMS-986165 at all and instead concerns completely unrelated compounds: the '208 publication discloses "solid formulations of enzalutamide" ('208 publication, 03), and
Tajarobi discloses formulations of butyl paraben (Tajarobi, p. 126). Each of these compounds is structurally distinct from BMS-986165. See '208 publication, 04 (showing structure of enzalutamide) and Tajarobi, Fig. 1 (showing structure of butyl paraben).
Examiner disagrees for the following reasons: In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., bioavailability and stability challenges for the specific compound BMS-986165 are disclosed only in the present application (see, e.g., page 7, line 28 - page 8, line 7, and page 3, line 18 - page 4, line 7 of the specification as originally filed) are not recited in the rejected claim(s).
Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Also, the combination of the references used teaches the following:
Papp teaches BMS-986165 is a potent, oral TYK2 inhibitor that binds to the pseudo-kinase domain of the enzyme and is functionally more selective than other tyrosine kinase inhibitors (Papp, pg. 1314, col.1, full para 2). This is the same inhibitor that is used in the Instant Application. It also discloses the patients were given an oral dosage form of BMS986165 for treatment. As such, the functional language is met for this part of the claims.
Pub’208 teaches formulations of an API as it relates to solid formulations comprising an amorphous API (which can be substituted with BMS-986165, paras. [0020-0030]). This oral formulation can be prepared by other known means - including spray-drying and has an internal and external phase made of the same polymers used in the Instant Application. This creates a solid dispersion containing an API and polymer. The disclosure relates to methods for manufacturing such formulations and compositions, and their use.
Tajarobi discusses the influence of the crystallization inhibition of HPMC and HPMCAS. As stated in the abstract of Tajarobi “One of the drawbacks with solid solution systems is their thermodynamic instability in solution. Considering the release of these systems from extended-release formulations, in particular swellable matrix tablets, a successful tablet formulation can be regarded as a composition able to maintain the molecular state of the poorly soluble crystalline drug through diffusion in the matrix.”
It is with the combination of these references, accessible to one in the art, that an obvious combination of existing ideas or prior art. Specifically, the 103 rejection indicates that the claimed invention is not sufficiently inventive over what already exists, and it does not require a single reference to match the idea word-for-word.
Hence, a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
In the weight of this evidence, Examiner still states it is obvious with this combination of references used; the Applicant’s arguments are not persuasive.
In response to Applicant’s overall arguments that:
Furthermore, there is no disclosure in the '208 publication or in Tajarobi to suggest that the formulations disclosed therein would be suitable or appropriate for other compounds generally, let alone BMS-986165 specifically, and there otherwise is no guidance in the cited art that would have led the person of ordinary skill in the art to combine the compound BMS-
However, even if amorphous solid solutions using the polymers HPMC and HPMCAS might have been known, that does not support the conclusion that a person of ordinary skill in the art would have had a reason to use the polymers with the specific compound BMS-986165, or would have had a reasonable expectation of success in doing so.
Examiner disagrees for the following reasons: In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Also, the combination of the references used teaches the following:
Papp teaches BMS-986165 is a potent, oral TYK2 inhibitor that binds to the pseudo-kinase domain of the enzyme and is functionally more selective than other tyrosine kinase inhibitors (Papp, pg. 1314, col.1, full para 2). This is the same inhibitor that is used in the Instant Application. It also discloses the patients were given an oral dosage form of BMS986165 for treatment. As such, the functional language is met for this part of the claims when the rejection is considered as a combination of references.
Pub’208 teaches formulations of an API as it relates to solid formulations comprising an amorphous API (which can be substituted with BMS-986165, paras. [0020-0030]). This oral formulation can be prepared by other known means - including spray-drying and has an internal and external phase made of the same polymers used in the Instant Application. This creates a solid dispersion containing an API and polymer. The disclosure relates to methods for manufacturing such formulations and compositions, and their use.
Tajarobi discusses the influence of the crystallization inhibition of HPMC and HPMCAS. As stated in the abstract of Tajarobi “One of the drawbacks with solid solution systems is their thermodynamic instability in solution. Considering the release of these systems from extended-release formulations, in particular swellable matrix tablets, a successful tablet formulation can be regarded as a composition able to maintain the molecular state of the poorly soluble crystalline drug through diffusion in the matrix.”
It is with the combination of these references, accessible to one in the art, that an obvious combination of existing ideas or prior art. Specifically, the 103 rejection indicates that the claimed invention is not sufficiently inventive over what already exists, and it does not require a single reference to match the idea word-for-word.
Hence, a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
In the weight of this evidence, Examiner still states it is obvious with this combination of references used; the Applicant’s arguments are not persuasive.
IV. New Rejections –
The prior 103 was withdrawn due to the additional limitation added to Independent Claim 2. The independent claim has 112 issues which need to be addressed.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION. —The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 2 is 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 2 contains the trademark/trade name Eudragit L 100-55. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product.
A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe an anionic copolymer made of methacrylic acid and ethyl acrylate; a registered trademark of Evonik (formerly Evonik Röhm GmbH) and, accordingly, the identification/description is indefinite.
Claim Interpretation
Claim 2, under Broadest Reasonable Interpretation, states “A dosage form for extended release of … (BMS-986165), the dosage form comprising:
an internal phase comprising a spray-dried dispersion of BMS-986165 in a polymer matrix; wherein the polymer matrix comprises one or more of: hydroxypropyl methylcellulose (HPMC), hypromellose phthalate (HPMC-P), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and
(ii) an external phase comprising a release-controlling polymer…”.
The claims provide a solid dispersion having the properties of BMS-986165 in a formulation for oral administration. The dosage form is a pharmaceutical formulation that contains an active pharmaceutical ingredient (API) along with other substances (excipients). Hence it is understood Claim 2 contains the amorphous dispersion which has dissolution stability
includes a drug and a polymer, where the drug is non-crystalline. The Instant Specification at pg. 7, lns 7-27 teaches various techniques for solid dispersions of an amorphous drug in a polymer as does the prior art.
Additionally, the transitional term used in the limitation of comprising “…the dosage form comprising: (i) an internal phase comprising a spray-dried dispersion of BMS-986165 in a polymer matrix; and (ii) an external phase comprising a release-controlling polymer…” is considered open-ended according to:
MPEP 2111.03.I:
The transitional term “comprising”, which is synonymous with “including,” “containing,” or “characterized by,” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See, e.g., Mars Inc. v. H.J. Heinz Co., 377 F.3d 1369, 1376, 71 USPQ2d 1837, 1843 (Fed. Cir. 2004) (“[L]ike the term ‘comprising,’ the terms ‘containing’ and ‘mixture’ are open-ended.”).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Graham vs. Deere, Test for Obviousness
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.
Joint Inventors
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.
Claims 2, 18-19, 22-37 are rejected under 35 U.S.C. 103 as being unpatentable over K. Papp, et. al (N Engl J Med. 2018 Oct 4;379(14):1313-1321; hereinafter “Papp”) and in view of WO 2014/043208 Al (hereinafter “Pub’208”) and in further view of F. Tajarobi, et al (Eur J Pharm Biopharm. 2011 May;78(1):125-33; hereinafter “Tajarobi”).
With respect to Claim 2, Papp recites a dosage form of an API BMS-986165, (pg. 1313, Abstract-Methods) for the oral dosage form “patients were randomly assigned to one of five oral doses of BMS-986165 (3 mg every other day, 3 mg daily, 3 mg twice daily, 6 mg twice daily, or 12 mg daily) or matching oral placebo in a ratio of 1:1:1:1:1:1. Capsules of the active drug (3 mg) or matched placebo were combined as appropriate to provide the required daily dose and were taken each morning and again 12 hours later” (pg. 1314, col. 2, full para. 2). Papp further discloses that the results of “the phase 2 trial indicates phase 2 trial of BMS-986165 indicate a therapeutic benefit of an oral selective TYK2 inhibitor” (pg. 1320, col. 1, hanging para. 1).
Under Broadest Reasonable Interpretation, this reads on also as disclosed on pg. 1314, col. 2, full para. 2, “capsules of the active drug (3 mg) or matched placebo were combined as appropriate to provide the required daily dose in a ratio of 1:1:1:1:1:1.”
It is implicit under BRI that the dosage form of the BMS-986165, used in the Papp prior art, contains the dose of BMS-986165 at 3, 6 and 9 mgs. Though the dosage varies from subject group to subject group, clinical condition of the subject, the severity of any disorder being treated and the like. Treatment involves daily or multi- daily doses of compound(s) over a period of time (demonstrating time-release capabilities such as an internal/external phase polymer). The dosage form is a pharmaceutical formulation with an active pharmaceutical ingredient (API) along with other substances (excipients).
The Instant Application does not demonstrate a non-obvious improvement over existing formulations, such as enhanced stability, improved bioavailability, or a new controlled-release mechanism. In this understanding, they are obvious when features of the claimed formulation are found in the prior art, even if the features or characteristics of the formulation are not explicitly disclosed in the prior art.
As seen in Papp, the prior art discloses a phase 2, double-blind trial of a TYK2 inhibitor, BMS-986165, with patients orally administrated the drug at a dose of 3 mg every other day, 3 mg daily, 3 mg twice daily, 6 mg twice daily, or 12 mg daily or to receive placebo (pg. 1314, col. 1, para. 1). The dosage form of the clinical trial mentions an active pharmaceutical ingredient (API) which is also understood to have additional substances (excipients, such as internal/external coating; demonstrating there is some type of polymer allowing for ease of ingestion) as noted by the oral administration.
Papp does fail to disclose: “(i) an internal phase comprising a spray-dried dispersion of BMS-986165 in a polymer matrix; wherein the polymer matrix comprises one or more of: hydroxypropyl methylcellulose (HPMC), hypromellose phthalate (HPMC-P), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and (ii) an external phase comprising a release-controlling polymer, wherein the release-controlling polymer is hydroxypropyl methylcellulose and mixtures thereof.”
WIPO publication ’208 discloses, in several embodiments (paras. [0135]- [0140]): “[0135] – the overall dosage form or particles, granules or beads that make up the dosage form may have superior performance if coated with an enteric polymer to prevent or retard dissolution until the dosage form leaves the stomach. Exemplary enteric coating materials include hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate… [0138] - embodiments, of compositions are delivered using a coated osmotic controlled release dosage form. This dosage form has two components:
(a) the core which contains an osmotic agent and the dispersion of enzalutamide (can be substituted for another API, BMS-986165) and concentration enhancing polymer; and
(b) a non-dissolving and non-eroding coating surrounding the core, the coating controlling the influx of water to the core from an aqueous environment of use so as to cause drug release by extrusion of some or all of the core to the environment of use….”
With respect to Claims 18, Pub’208 discloses in para. [0053], that amphiphilic polymers interact with a drug to prevent the precipitation or crystallization of the said drug from solution despite its concentration being substantially above its equilibrium concentration.
Using Broadest Reasonable Interpretation, Pub’208 gives the example of the API drug in para. [0053] – enzalutamide – in a polymer/drug assembly, the drug “clusters surrounded by the polymer with the polymer's hydrophobic regions turned inward towards the enzalutamide and the hydrophilic regions of the polymer turned outward toward the aqueous environment”.
This reads on Claim 18 wherein the external phase further comprises a crystallization inhibitor. More specifically it is also disclosed in para. [0053], the interaction of the drug of choice with the polymer described prevents the precipitation or crystallization of the drug. This is understood as a crystallization inhibitor. “In addition, such amphiphilic polymers interact with enzalutamide to prevent the precipitation or crystallization of the enzalutamide (drug of prior art) from solution despite its concentration being substantially above its equilibrium concentration. In some embodiments, when the compositions are solid amorphous dispersions of enzalutamide and the concentration-enhancing polymer, the compositions provide a greatly enhanced drug concentration, particularly when the dispersions are substantially homogeneous.”
With respect to Claim 2 & 19 Pub’208 discloses wherein the crystallization inhibitor is selected from polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, and mixtures thereof (paras. [0061]- [0062]).
With respect to Claim 2, Pub’208 discloses wherein the polymer matrix comprises hydroxypropyl methylcellulose acetate succinate (HPMCAS), (paras. [0072] and [0061]-[0062]), and the release-controlling polymer comprises hydroxypropyl methylcellulose (HPMC), (paras. [0006], [0072], and [0061]- [0062]; also, Example 14, paras. [0207]- [0220]– Tablet 14.1; pg. 64).
With respect to the following claims 25-37, Pub’208 can be used substituting API for API, and the prior art overlaps with the instant claimed range for dose, as the API concentration can be calculated (paras. [0037-0047]) particularly as Pub’208 provides Maximum Drug Concentration calculation. This indicates that BMS-986165 (deucravacitinib) can be used via KSR-Prong B:
Claim 25: Pub’208 teaches wherein the spray-dried dispersion comprises the API in an amount that is in the range of from 5% to 25% w/w of the spray- dried dispersion. (Ex. 2 & Table 2.1, para. [0172-0173])
Claim 26: Pub’208 teaches wherein the spray-dried dispersion comprises the API in an amount that is in the range of from 5% to 25% w/w of the spray- dried dispersion. (Ex. 2 & Table 2.1, para. [0172-0173])
Claim 27: Pub’208 teaches wherein the amount of the API in the oral dosage form is from 12 to 36 mg (lower end of the range of para. [0026]).
Claim 28: Pub’208 teaches wherein the amount of the API in the oral dosage form is from 12 to 36 mg (lower end of the range of para. [0026]).
Claim 29: wherein the amount of BMS-986165 in the oral dosage form is from 12 to 36 mg (lower end of the range of para. [0026]).
Claim 30: Pub’208 teaches wherein the amount of the API in the oral dosage form is 15 mg (lower end of the range of para. [0026]).
Claim 31: Pub’208 teaches wherein the amount of the API in the oral dosage form in the oral dosage form is from 12 to 36 mg (lower end of the range of para. [0026]).
Claim 32: Pub’208 teaches wherein the amount of the API in the oral dosage form is 15 mg (lower end of the range of para. [0026]).
Claim 33: Pub’208 teaches wherein the amount of the API in the oral dosage form is from 12 to 36 mg (lower end of the range of para. [0026]).
Claims 34-37: Pub’208 teaches wherein the oral dosage form is a tablet (para. [0090-0091).
Thus, based on the above combination of Papp and Pub’208, one would be motivated/given suggestion through the art and use of KSR – Prong B to substitute the API drug of the prior art with Papp’s API compound BMS-986165 (also that of the Instant Case) in a polymer/drug assembly. The drug used in Papp is the identical compound used in the Instant Claims, so overlap in utility of BMS-986165 is demonstrated. Pub’208 also has embodiments of the Instant claimed polymers used as water-soluble polymer such as HPMC, and for HMPCAS prepared by spray drying method, which improve aqueous solubility and bioavailability.
However, it would have been obvious to one having ordinary skill in the art to arrive at an overlapping range because according to MPEP 2144.05:
Overlapping ranges-
In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) (The prior art taught carbon monoxide concentrations of “about 1-5%” while the claim was limited to “more than 5%.” The court held that “about 1-5%” allowed for concentrations slightly above 5% thus the ranges overlapped.); In re Geisler, 116 F.3d 1465, 1469-71, 43 USPQ2d 1362, 1365-66 (Fed. Cir. 1997) (Claim reciting thickness of a protective layer as falling within a range of “50 to 100 Angstroms” considered prima facie obvious in view of prior art reference teaching that “for suitable protection, the thickness of the protective layer should be not less than about 10 nm [i.e., 100 Angstroms].” The court stated that “by stating that ‘suitable protection’ is provided if the protective layer is ‘about’ 100 Angstroms thick, [the prior art reference] directly teaches the use of a thickness within [applicant’s] claimed range.”).
This and the combination of HMPC and HPMCAS used in dosage form for BMS-986165 is further explained in the prior art as seen by Tajarobi. This use of the polymer encompasses the extended-release formulation recited in the Instant Claims. It teaches in the prior art just how important the combination of polymers is important to allow for extended release of an oral formula but one that can be used on an oral dosage of BMS-986165 (pg. 126, col 1, Materials and methods “Hydroxypropyl methylcellulose (HPMC:Shin-Etsu Chemical Co., Ltd., Tokyo, Japan, grade 90SH100 SR) and hydroxypropyl methylcellulose acetate succinate (HPMCAS:
ShinEtsu AQOAT®, Type AS-MF) were used as solid dispersion carrier and matrix former in the extended-release swellable tablets).
Tajarobi further discloses “an optimum formulation approach for improving bioavailability can be to deliver the drug substance from the matrix in a form that is already dissolved or readily dissolvable in the gastrointestinal tract” (pg. 125, col. 1, para. 1). Tajarobi continues to discloses “one of the most commonly encountered types of solid dispersions is amorphous solid solutions. In these systems, the drug substance is molecularly distributed within
the amorphous carrier. One type of amorphous carrier, which have recently grown in popularity, is cellulose derivatives such as hydroxypropyl methylcellulose (HPMC) and hydroxypropyl
methylcellulose acetyl succinate (HPMCAS) (pg. 125, col. 2, full para. 1).”
As BMS-986165 has been known since 2014 (as evidenced by the STN search attached with this action), it is known BMS-986165 (deucravacitinib) formulated in a polymer matrix typically exists as an Amorphous Solid Dispersion (ASD). This technique disperses the drug in an inert polymer carrier to prevent crystallization, vastly improving the solubility and bioavailability of the medication when taken orally for autoimmune conditions.
As such, combination of the prior art of Papp (using Phase 2 trials of an oral dosage form of BMS-986165 to a patient population), the drug/polymer assembly of Pub’208 (using polymers HMPC and/or HPMCAS for external and internal phase coating, the dosage form as tablets, dosage range, spray-dried dispersion range), and explanation of Tajarobi (in the determination of how the influence of crystallization inhibition of HPMC and HPMCAS on substance dissolution and release in swellable matrix tablets and as extended-release tablets) can motivate and suggest to one the claims of the Instant Specification due to KSR – Prong A, as well as substitution through KSR – Prong B to arrive at the Instant Claims
Considering the release of drug extended-release formulations, in particular swellable matrix tablets, a successful tablet formulation can be regarded as a composition able to maintain the molecular state of the poorly soluble crystalline drug through diffusion in the matrix. It is well known that for some products, controlled drug release is a prerequisite for desired clinical outcome. Therefore, solid dispersions in different types of extended-release formulations is desirable, as seen by the prior art combination.
Tajarobi finishes teaching for the following claims 22-24 the following:
Claim 22: Tajarobi teaches wherein the polymer matrix comprises hydroxypropyl methylcellulose acetate succinate (HPMCAS). Tajarobi - (pg. 125, col. 1-2, full para. 1)
Claim 23. Tajarobi teaches wherein the polymer matrix comprises hydroxypropyl methylcellulose acetate succinate (HPMCAS), and wherein the release-controlling polymer comprises hydroxypropyl methylcellulose (HPMC). Tajarobi - (pg. 125, col. 1-2, full para. 1)
Claim 24: Tajarobi teaches wherein the polymer matrix comprises hydroxypropyl methylcellulose acetate succinate (HPMCAS), wherein the release-controlling polymer comprises hydroxypropyl methylcellulose (HPMC), and wherein the crystallization inhibitor comprises hydroxypropyl methylcellulose acetate succinate (HPMCAS). Tajarobi - (pg. 125, col. 1-2, full para. 1).
Conclusion
Claims 2, 18-19 and 22-37 are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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Josmalen M. Ramos-Lewis, Ph.D.
Patent Examiner
Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
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