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 .
This application is a CON of Application No. 17765934 that claims earliest foreign priority to EP 19201339.9 with a priority date of 10/03/2019.
Status of Clams
Claims 1-15 and 17-21 are pending.
Election/Restrictions
Applicant's election with traverse of Group I, claims 1-12 and 19-21 in the reply filed on June 17, 2025 is acknowledged. The traversal is on the ground that the analysis of a special technical feature is believed to be misplaced, in view of Rule 475(b), and in any event is not factually accurate, as WO 2014043208 does not place a coprecipitate on a substrate.
This is not found persuasive for the reasons recited in the Restriction Requirement dated April 17, 2025.
Applicant’s election of the species of Table 1 is acknowledged. The elected species of Table 1 reads upon claims 1-7, 10-12, and 19. The requirement for species election is modified to include microcrystalline cellulose (MCC) as a substrate.
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The requirement is still deemed proper and is therefore made FINAL.
Claims 8, 9, 13-15, 17-18 and 20-21 withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on June 17 2015.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on April 1 2022 was filed is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
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.
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.
Claims 1-4, 6-7, 10-12, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2014/043208 A1 (WO 208). WO 208 is cited on the IDS.
Examined claim 1 is a tablet composition comprising a granulate consisting of a coprecipitate on a substrate, wherein the co-precipitate comprises enzalutamide in amorphous form and a cellulosic concentration enhancing polymer.
In terms of claim interpretation, the specification teaches co-precipitation of enzalutamide (ENZ) and a polymer (such HMPCAS) at step a) of the process of page 9. See also claim 11, step a). While the specification notes the tablet comprises a granulate formed by co-precipitation of ENZ and HMPCAS, claim 1 is interpreted to be a tablet formulation comprising a granulate (whether formed by the art recognized process of co-precipitation or not), with the required enzalutamide in granule with a polymer (HPMCAS) and a substrate of microcrystalline cellulose (MCC) in the claimed ratio range of 1 : 2 : 0.5 to 1: 6 : 5, respectively.
Further, the specification recognizes the unique challenges of formulating enzalutamide, where it states “Enzalutamide is a BCS class II1 compound, exhibiting low solubility [in water, i.e., aqueous solvents] and high permeability [easily pass thru cell membranes and are easily absorbed by the body].” See specification at page 2, lines 5-6.
Prior art recognizing these tablet limitations and recognizing the unique challenges of formulating enzalutamide tablets would have been relevant to a person having ordinary skill in the art (PHOSITA) in the obviousness analysis.
To address the recognized low solubility issue, WO 208 teaches formulating “a suitable single tablet of reasonable size comprising the prescribed amount of enzalutamide and having suitable and advantageous solubility and/or dissolution stability and absorption would be advantageous as a suitable alternative to soft capsules.” Id. at paragraph 5.
While not specifically recited by claim 1, it is noted that ENZ and the concentration enhancing polymer HPMCAS component of claim 1 is formed by dissolving both in acetone. See page 9, step a) of the process recited therein. See also process claim 11, step a).
Similar to this process, WO 208 recognized the solubility issue of enzalutamide, dissolves it with acetone, and/or mixtures with water. See paragraphs 79, 145, and Example 2 entitled (Preparation of enzalutamide dispersions with concentration enhancing polymers [example used therein HPMCAS].
The below claim chart highlights examined claim 1’s limitations and how they are taught by Table 14.1 of WO 208.
Claim 1 Limitations
See Table 14.1. Tablet Composition
tablet composition comprising
a granulate consisting of a co-precipitate (comprises amorphous enzalutamide (ENZ) and a polymer,[such as hydroxylpropylmethylcellulose acetate succinate (HPMCAS)] on a substrate
266.7 grams of 60% amorphous (A) enzalutamide(ENZ) / HPMCAS-M-SDD (spray dry dispersions)
The ENZ SDD was formed dissolving it with acetone along with the polymer HPMCAS, as per claims 36, 37 and 38.
wherein the substrate comprises, for example, a sugar alcohol, microcrystalline cellulose, or
mixtures thereof.
See Example 14, Table 14.1 noting the presence of 94.8 grams microcrystalline cellulose (MCC, aka Avicel® PH102)
Table 14.1 does not teach a granulate co-precipitate of amorphous enzalutamide and a polymer such as HPMCAS with other excipients. However, following the teachings of WO 208 a person having ordinary skill in the art (PHOSITA) would find it prima facie obvious to formulate such a granulate co-precipitate of amorphous ENZ and HMPMCAS with other excipients, the rationale to do so being it discloses granules for formulation into tablets as taught in WO 208 as follows.
WO 208’s claim 95 teaches a process for manufacturing enzalutamide and polymer tablets where (1) a solid dispersion of enzalutamide and polymer is formed, (2) the solid dispersion of enzalutamide and polymer is mixed with additives to form a granulating mixture and (3) tableting the mixture.
Further, WO 208 teaches its spray dried dispersion post solidification, stays as a solid powder in its spray drying chamber to further evaporate solvent from it. See paragraph 81. Subsequently, the dried powder is preferably sprayed with a solvent or polymer solution or other excipient to form granules. Id. at paragraph 81. Note that paragraph 81 discloses the spraying of polymer or other excipient into the spraying drying chamber to form granules, where it would be with the purview of a PHOSITA to routinely optimize a spraying of a co-precipitate of polymer, ENZ and substate, where the ENZ and polymer co-precipitate when sprayed with a substate would form the claimed granulate consisting of a co-precipitate on a substrate.
Alternatively, the tablet formulation of Table 14.1, while being a dry powder direct compression, methods of forming solid pharmaceutical composition as granulate via dry granulation are also routine for a PHOSITA to routinely optimize to predictably arrive at the claimed invention. See paragraph 151. The granulate of claims 1 and 14, consisting of a co-precipitate on a substrate, could be formed by the dry granulation of paragraph 151, where the dry mixing and granulation of co-precipitate with a excipient/substrate would result in the claimed granulate consisting of co-precipitate on a substrate.
A PHOSITA would routinely optimize the teachings of Table 14.1 as per the granulation methods of as per claim 95 and paragraphs 81 and 151.
Regarding claim 2 and the disclosed range of 1 :2 to 1:6, WO 208 teaches an overlapping range is disclosed by WO 208. Claim 23 discloses adjustment of amounts of ENZ to at least about 20%, which would result in a 4: 1 ENZ : polymer ratio that falls within the range claimed of 1:2 to 1: 6.
While Table 14.1 does not teach the exact ratio of ENZ : polymer (e.g., HPMCAS or HPMCP) : substrate as claimed, per MPEP 2144.05 I.-II.2, it would be prima facie obvious for a PHOSITA to adjust the ranges of the particular ratios of ENZ : polymer ratio as taught WO 208. Paragraph 88 of WO 208 teaches such adjustment of range, as well as a basis to adjust such ranges as follows.
“[t]he amount of concentration-enhancing polymer relative to the amount of enzalutamide present in the dispersions may vary widely. The composition of enzalutamide/polymer dispersions is expressed, for example, as 25%A:HPMCAS-M, where 25%A means "25% active" and the dispersion contains 25% (by weight) enzalutamide and 75% (by weight) hydroxypropylmethlycellulose acetate succinate M-grade. In enzalutamide dispersions described herein, the enzalutamide content is generally greater than 20%A; in some embodiments, from 25%A to 75%A; in some embodiments, from 50%A to 70%A. For a specific concentration-enhancing polymer, the enzalutamide/polymer ratio that yields optimum results is best determined in in vitro dissolution tests and/or in vivo bioavailability tests.
Regarding claim 3 and the limitation of HMPCAS and HPMCP as claimed, WO 208 teaches ENZ along with a polymer HMPMCAS as detailed above. See Example 14, Table 14.1 on page 64, below.
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Regarding claim 4 and the limitation of microcrystalline cellulose (MCC), WO 208 teaches MCC as detailed above. See Example 14, Table 14.1 on page 64, detailed above.
Regarding claims 6-7 and the limitation of disintegrant, such as croscarmellose sodium, this is taught by WO 208 in Table 14.1.
Regarding examined claims 10-11 further comprising pharmaceutically acceptable excipients wherein the pharmaceutically acceptable excipients are selected from one or more diluents, disintegrants, glidants or lubricants, it is noted WP 208’s Table 14.1 teaches these excipients as follows.
WO 208 teaches that examples of diluents include these two ingredients of Table 14.1, lactose. See paragraph 124.
WO 208 teaches that colloidal silicon dioxide of Table 14.1 is a glidant. See paragraphs 93 and 119.
WO 208 teaches croscarmellose sodium of Table 14.1 is a disintegrant. See claim 33.
Regarding claim 12 and the dissolution rate properties recited therein, WO 208 does not teach this limitation that further limits the tablet of claim 1.
However, per MPEP 2112.01 II.3, “A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id.” citing In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
As WO 208 teaches the claimed tablet of claim 1, the dissolution rate properties of claim 10 are necessarily present in its tablet formulation of Table 14.1.
Regarding examined claim 19 and the limitation therein, reference application claim 17 discloses wherein the substrate is selected from a sugar alcohol, microcrystalline cellulose or mixtures thereof, MCC is taught in WO 208’s Table 14.1 on page 64, see above.
Claims 1-7, 10-12, and 19 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO 2014/043208 A1 (WO 208) in view of WO 2015/118015 (WO 015) . WO 208 and WO 015 are cited on the IDS.
It is noted that where WO 208 renders the claims 1-4, 6-7, 10-12 and 19 obvious, it does not teach the particular species of claims 1-7, 10-12 and 19, where the substrate or filler species of claim 5, is the sugar alcohol, mannitol.
However, a PHOSITA following the teachings of WO 208 disclosing the claimed tablet comprising the claimed enzalutamide (ENZ) granulate would have found it prima facie obvious to use mannitol as a substrate as taught by WO 015 for ENZ solid formulations, where the prior art teaches these fillers/substrates are prior art recognized as alternatives for one another. See bottom of page 21 bridging to top of page 22, where fillers listed include not only microcrystalline cellulose but also sugar alcohols such as mannitol. A PHOSITA would have a rationale to do so as the formulations of WO 015 are directed to enzalutamide compositions. See claims 1-11.
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 claims because the examined application claim is either anticipated by, or would have been obvious over, the reference claims. 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 1-7, 10-12, and 19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims of copending Application No. 18/762,066 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because they are both directed to the same enzalutamide tablet formulation.
Examined claim 1 requires a tablet composition comprising a granulate consisting of a coprecipitate on a substrate, wherein the co-precipitate comprises enzalutamide in amorphous form and a cellulosic concentration enhancing polymer.
As required by examined claim 1, reference claim 1 discloses a tablet formulation of a granulate co-precipitate of enzalutamide in amorphous form and a cellulosic concentration enhancing polymer selected from hydroxylpropylmethylcellulose acetate succinate (HPMCAS) and hydroxypropylmethylcellulose phthalate (HPMCP);
a substrate comprising a sugar alcohol (mannitol), microcrystalline cellulose, (MCC), or mixtures thereof, where the weight ratio of enzalutamide to polymer to substrate is in the range of 1 : 2: 0.5 to 1 : 6 : 5, respectively.
While reference claim 1 teaches the required elements of examined claim 1 elements of
a tablet comprising
a granulate consisting of a coprecipitate on a substrate
wherein the co-precipitate comprises amorphous enzalutamide and cellulosic concentration enhancing polymer; reference claim 1 only narrowly claims two particular cellulosic concentration enhancing polymers, HMPCAS and HPMCP.
However a person one of ordinary skill in the art (PHOSITA) is guided by the teaching of HMPCAS and HPMCP to arrive at cellulosic enhancing polymers as a class generally since two are taught and claimed by the reference application.
The rationale to do so are the teachings of HMPCAS and HPMCP and two members of the class of polymers to allow a PHOSITA to arrive various cellulosic concentration enhancing polymers.
Regarding claim 2 and the disclosed range of 1 :2 to 1:6, reference application claim 1 discloses the overlapping weight ratio of enzalutamide to polymer to substrate is in the range of 1 : 2: 0.5 to 1 : 6 : 5.
Regarding examined claim 3, reference application claim 1 discloses HMPCAS and HPMCP as claimed.
Regarding examined claim 4, reference application claim 1 discloses microcrystalline cellulose (MCC) as claimed. See also claim 3.
Regarding examined claim 5, reference claim 2 discloses the sugar alcohol mannitol. See claim 2.
Regarding examined claims 6-7, wherein the substrate further comprises a disintegrant, such as croscarmellose sodium, claims 5-6 of the reference application teach croscarmellose as a disintegrant..
Regarding examined claims 10-11 wherein the pharmaceutically acceptable excipients are selected from one or more diluents, disintegrants, glidants or lubricants, reference application claims 8-9 teaches these excipients of diluents, disintegrants, glidants or lubricants.
Regarding examined claim 12 wherein the composition exhibits a dissolution rate of less than 15% in 30 minutes when tested in 300 ml 0.03 N hydrochloric acid pH 1.2 and at least 75% in 90 minutes when tested in 900 ml phosphate buffer pH 6.8 in a USP apparatus II at 50 rpm (normal vessel), 37°C, reference application claim 10 discloses these limitations.
Regarding examined claim 19 and the limitation therein, reference application claim 17 discloses wherein the substrate is selected from a sugar alcohol, microcrystalline cellulose or mixtures thereof.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to WILLIAM LEE whose telephone number is (571)270-3876. The examiner can normally be reached M-F.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam C. Milligan can be reached at (571) 270-7674. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/WILLIAM Y LEE/Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623
1 See Pion webpage “What are BCS Class I drugs?” accessed Dec 7 2024, reproduced below.
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https://www.pion-inc.com/blog/what-are-bcs-class-ii-drugs#:~:text=BCS%20stands%20for%20Biopharmaceutics%20Classification,high%20permeability%20but%20low%20solubility.
2 See MPEP 2144.05 Obviousness of Similar and Overlapping Ranges, Amounts, and Proportions [R-01.2024]
OVERLAPPING, APPROACHING, AND SIMILAR RANGES, AMOUNTS, AND PROPORTIONS
ROUTINE OPTIMIZATION
3 See MPEP 2112.01 II.(COMPOSITION CLAIMS — IF THE COMPOSITION IS PHYSICALLY THE SAME, IT MUST HAVE THE SAME PROPERTIES)