DETAILED ACTION
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on January 12 2026 has been entered.
Receipt of Arguments/Remarks filed on January 12 2026 is acknowledged. Claims 8-9, 12, were/stand cancelled. Claims 1, 5 and 24 were amended. Claims 28-30 were added. Claims 1-7, 10-11, 13-30 are pending. Claim 23 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on March 12 2025. Claims 1-7, 10-11, 13-22 and 24-30 are directed to the elected invention.
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 .
Withdrawn Objections/Rejections
The declaration filed January 12 2026 is sufficient to overcome the rejection of claims 1-7, 10-22 and 24-27 under 35 U.S.C. 103 as being unpatentable over Barrett et al. (WO2017196697, cited on PTO Form 1449) in view of Patel et al. (WO2018067882), Skomski et al. (WO2020131649, cited on PTO Form 1449) and Kuzma et al. (US20120231061). The declaration clearly sets forth that Skomski et al. is not available as prior art via the 102(b)(2)(C) exception. Therefore, the arguments with regards to Skomski et al. have been considered and are persuasive.
The amendments filed January 12 2025 are sufficient to overcome the rejection of claims 1-7, 10-18, 20-22 and 24-27 under 35 U.S.C. 103 as being unpatentable over Barrett et al. (WO2017196697, cited on PTO Form 1449) in view of Patel et al. (WO2018067882), Kuzma et al. (USPGPUB No. 20120231061) and Kohgo et al. The claims require a crystalline 4’-ethynyl-2-fluoro-2’-deoxyadenosine anhydrate which is not taught in the cited prior art. Therefore, Applicants arguments with regards to this rejection are considered and are persuasive.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 28-29 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The term “low melting” in claims 28-29 is a relative term which renders the claim indefinite. The term “low-melting” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The instant specification contains one instance of the recitation “low-melting thermoplastic polyurethane” in Table 2 and refers to LM-TPU in Table 2/3. But the specification never indicates what is meant by “low melting”. Presumably this corresponds to the melting point of the polymer. But the specification never contemplates the scope that makes a thermoplastic polyurethane “low-melting” compared to other thermoplastic polyurethanes. Kuzma et al. (USPGPUB 20120231061, previously cited) teaches polyurethanes are made of soft segments and hard segments. It is taught that soft segments are low-melting (paragraph 0024). Thus manipulation of the melting point of the polyurethane can occur via changes in the concentration of the soft segments and hard segments (high-melting point). But the specification does not indicate at what concentration of soft segments is required to achieve a low-melting point polyurethane or how to determine if there are a sufficient number of soft segments such that the polyurethane is now low-melting. The specification does not disclose any commercial sources for the polyurethane which could be used to determine the scope of the claimed polyurethanes.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 19 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 19 depends from claim 1. Claim 1 recites a crystalline 4’-ethynyl-2-fluoro-2’-deoxyadenosine anhydrate. Figure 1 indicates that the powder x-ray diffraction is for crystalline 4’-ethynyl-2-fluoro-2’-deoxyadenosine anhydrate. Since the x-ray diffraction pattern is describing the crystalline compound in claim 1, it does not appear that claim 19 further limits the structure but merely recites a property of the crystalline 4’-ethynyl-2-fluoro-2’-deoxyadenosine anhydrate already recited in claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim 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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 1-7, 10-11, 13-18, 20-22 and 24-30 are rejected under 35 U.S.C. 103 as being unpatentable over Barrett et al. (WO2017196697, cited on PTO Form 1449) in view of Patel et al. (WO2018067882), Kuzma et al. (USPGPUB No. 20120231061) and Chang et al. (CN109893536, publication date 6/18/2019).
Applicant Claims
The instant application claims an implant drug delivery system comprising: (a) a core comprising a biocompatible nonerodible polymer comprising thermoplastic poly(urethane) and a crystalline 4'-ethynyl-2- fluoro-2'-deoxyadenosine anhydrate, wherein the 4'-ethynyl-2-fluoro-2'-deoxyadenosine anhydrate is present in the core between 1% and 60% by weight, and (b) a biocompatible nonerodible diffusional barrier comprising a polymer, wherein said diffusional barrier has a thickness between 50 pm and 300 pm, wherein said implant drug delivery system is adapted for subdermal implantation and 4'-ethynyl-2-fluoro-2'- deoxyadenosine anhydrate is continually released in vivo at a rate resulting in a plasma concentration of 4'-ethynyl-2-fluoro-2'-deoxyadenosine between 0.02 ng/mL and 300.0 ng/mL for a period of six months to thirty-six months.
As elected the diffusion barrier is poly(urethane).
The examiner notes that the specification indicates that 4'-ethynyl-2-fluoro-2'-deoxyadenosine is also known as islatravir (see page 9 of the instant specification).
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Barrett et al. is directed to a drug delivery system for the delivery of antiviral agents. Claimed is an implant drug delivery system comprising a biocompatible nonerodible polymer and 4'-ethynyl-2-fluoro-2'-deoxyadenosine wherein said implant drug delivery system is implanted subdermally and 4'-ethynyl-2-fluoro-2'-deoxyadenosine is continually released in vivo at a rate resulting in a plasma concentration between 0.02 ng/mL and 300.0 ng/mL (claim 1). Claimed the 4'-ethynyl-2- fluoro-2'-deoxyadenosine plasma concentration is between 0.02 ng/mL and 30.0 ng/mL (claim 2) or the 4'-ethynyl-2- fluoro-2'-deoxyadenosine the plasma concentration is between 0.02 ng/mL and 8.0 ng/mL (claim 3). The biocompatible nonerodable polymer is ethylene vinyl acetate copolymer (claim 7-8). The system further comprises a diffusional barrier (claim 10) wherein specific diffusional barriers claimed is poly(urethane) (claim 12). The concentration of the 4'-ethynyl-2-fluoro-2'-deoxyadenosine in the biocompatible nonerodable polymer (i.e. core) is between 0.10% to 80% by weight (claim 14). Exemplified formulations contain 30-50 wt% 4'-ethynyl-2-fluoro-2'-deoxyadenosine and specifically 30, 35, 40, 45, and 50 wt% (table 2). The diffusional barrier is a coating that is permeable to the drug and placed over at least a portion of the device to further regulate the release. The diffusional barrier may be formed by coextrusion with the device (page 4, lines 18-23). Extrusion temperatures range from 110-140 °C (example 1). The delivery system can further comprise a radiopaque component. The radiopaque component can be an element such as barium sulphate (page 5, lines 12-16). The 4'-ethynyl-2-fluoro-2'-deoxyadenosine is released at therapeutic concentrations for a duration from between 3 months and 36 months (claim 18). The implant is capable of releasing 4'-ethynyl-2-fluoro-2'-deoxyadenosine over a period of 21 days, one month, six months, etc. at an average range of between 0.02-8.0 ng per day (page 9, lines 24-30).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Barrett et al. suggests a diffusional barrier which can be made from poly(urethane), Barrett et al. does not teach a soluble filler or a thickness of the barrier. However, this deficiency is cured by Patel et al.
Patel et al. is directed to an implantable device for drug delivery with reduce burst release. Claimed is an implantable device for delivery of a pharmaceutical substance comprising a core comprising a first polymeric material and a pharmaceutical substance and a shell comprising a second polymeric material and a porogen (claim 1). Porogens include soluble material such as sodium chloride (claim 10). Second polymeric material include polyurethane (claim 52). The core and shell can vary independently in thickness. Thickness of the shell can be from about 0.125 mm to about 4 mm (125 microns to 4000 microns) (paragraph 0086). The mean diameter of the porogens can be between about 1 micrometer and about 300 micrometers. In some embodiments, the mean diameter of the porogens is equal to the thickness of the shell (paragraph 0112). It is taught that surrounding the drug-containing core with a porogen-containing shell can reduce the burst release often observed with sustained release formations. Use of a porogen material having a narrow size distribution and the resulting narrow size distribution of the pores left in the shell after removal of the porogen allows for better control and tuning of the release rate of the drug from the core (paragraph 0007).
While Barrett et al. suggests the core can be poly(urethane), Barrett et al. does not expressly teach a thermoplastic poly(urethane). However, this deficiency is cured by Kuzma et al.
Kuzma et al. is directed to long term drug delivery devices with polyurethane-based polymers and their manufacture. Taught is the use of thermoplastic polyurethane-based polymers to create implantable drug delivery device (paragraph 0057). The thermoplastic polyurethanes can be processed through extrusion (paragraph 0058). Example 1 teaches tecophilic polyurethanes which are a aliphatic polyether-based thermoplastic polyurethane that can be formulated to different equilibrium water contents of up to 150% of the weight of dry resin. It is taught that from the standpoint of drug release form these materials, the release of a relatively hydrophilic API (active pharmaceutical) increases as the % EWC increases (paragraph 0030). Polyurethanes contain two segments a hard segment and a soft segment (paragraph 0023). The soft segment is low-melting while the hard segment is high-melting (paragraph 0024). Varying the ratios of these two segments can alter the physical characteristics of the polyurethane (paragraph 0060). The release rates of the actives can also be controlled by the hydrophilicity/hydrophobicity of the polyurethane polymers (paragraph 0062).
While Barrett et al. suggests 4'-ethynyl-2-fluoro-2'-deoxyadenosine, Barrett et al. does not expressly teach crystalline 4'-ethynyl-2-fluoro-2'-deoxyadenosine anhydrate. However this deficiency is cured by Chang et al.
Chang et al. (wherein USPGPUB NO. 20230151048 is serving as a English Language equivalent) is directed to the crystal form, preparation method and application of 4’-substituted nucleoside. A specific compound taught is compound Ia:
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364
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which is 4'-ethynyl-2-fluoro-2'-deoxyadenosine (paragraph 0011). Fig. 7 is an x-ray powder diffraction spectrum of compound Ia. The crystal A of the compound Ia had diffraction peaks at 2θ angles (±0.2): 6.13, 7.77, 9.43, 10.61, 11.88, 12.44, 12.80, 13.88, 14.28, 14.66, 15.51, 17.09, 17.55, 17.88, 18.95, 21.18, 21.86, 22.40, 22.87, 23.52, 24.93, 25.69, 26.63, 28.60, 30.46 in a diffraction spectrum using CuKα radiation with a wavelength of λ=1.5418 Å (paragraph 0048). The compound Ia is better suitable to be a long-acting drug for prevention or treatment of HIV/AIDS (paragraph 0013).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Barrett et al., Patel et al., Kuzma et al. and Chang et al. and utilize the crystalline 4'-ethynyl-2-fluoro-2'-deoxyadenosine of Chang et al. One skilled in the art would have been motivated to utilize this form of 4'-ethynyl-2-fluoro-2'-deoxyadenosine as it is a known form of 4'-ethynyl-2-fluoro-2'-deoxyadenosine and is better suited to be a long-acting drug as taught by Chang et al. Since Barrett et al. teaches the use of 4'-ethynyl-2-fluoro-2'-deoxyadenosine and long-acting, one skilled in the art would have a reasonable expectation in utilizing any form of the compound such as solvates. Note: MPEP 2143 KSR International Co. v. Teleflex Inc., 550 US 398, 82 USPQ 2d 1385 (2007).
Regarding the claimed crystalline 4'-ethynyl-2-fluoro-2'-deoxyadenosine anhydrate in claim 1, 19 and 24, Chang et al. is silent to the anhydrate. Specifically, Chang et al. does not indicate a hydrate or anhydrate. But Chang et al. specifically teaches a crystalline structure. The x-ray diffraction pattern includes 2θ peaks at: 11.88, 12.44, 14.66 and 15.51. The 2θ error ranges are ± 0.2. This indicates that the XRPD of Chang et al., when taking into account the error ranges, has peaks at the same position as instantly claimed. Therefore, it appears that the same compound is taught in Chang et al.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Barrett et al., Patel et al., Kuzma et al. and Chang et al. and utilize a polyurethane diffusional barrier with porogens such as sodium chloride (reading on instantly claimed soluble filler) and a thickness of 1 micrometer to about 300 micrometers. One skilled in the art would have been motivated to utilize this diffusional barrier in order to surround the drug-containing core with a porogen-containing shell to reduce the burst release often observed with sustained release formations as taught by Patel et al. Since the use of a porogen material having a narrow size distribution and the resulting narrow size distribution of the pores left in the shell after removal of the porogen allows for better control and tuning of the release rate of the drug from the core, one skilled in the art would have been motivated to utilize this particular diffusional barrier. Since Barrett et al. suggests a polyurethane diffusional layer there is a reasonable expectation of success.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Barrett et al., Patel et al., Kuzma et al. and Chang et al. and utilize a thermoplastic polyurethane as the core material. One skilled in the art would have been motivated to utilize a thermoplastic polyurethane as Barrett et al. teaches the core material can be a polyurethane and Kuzma et al. teaches a thermoplastic polyurethane for a drug delivery implant. It would have been obvious to one of ordinary skill in the art to try known polyurethanes as a person with ordinary skill has good reason to pursue known options within his or her technical grasp. Note: MPEP 2141 KSR International CO. v. Teleflex Inc. 82 USPQ 2d 1385 (Supreme Court 2007).
Regarding the claimed thickness in claims 1, 15 and 24, Patel et al. teaches an overlapping range. 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). Note MPEP 2144.05. Furthermore, one skilled in the art would manipulate the shell thickness in order to achieve the desired release rate.
Regarding claims 2-7 and 22 Barrett et al. teaches an overlapping range for claimed concentration of 4'-ethynyl-2-fluoro-2'-deoxyadenosine anhydrate in the core and for the claimed plasma concentration and release time period. 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). Note MPEP 2144.05.
Regarding claim 14, Kuzma et al. teaches that the thermoplastic polyurethane that can be formulated to different equilibrium water contents of up to 150% and the precent water can control the release rate of the drug/API. Therefore, one skilled in the art would have been motivated to manipulate the structure of the thermoplastic polyurethane in order to achieve the desired water uptake and the desired release profile.
Regarding claims 17-18, Barrett et al. teaches co-extrusion and extrusion at a temperature of 110-140 °C which overlap the instant claims. 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). Note MPEP 2144.05.
Regarding claims 20-21, Barrett et al. teaches the inclusion of barium sulfate in the same concentration claimed.
Regarding the release rate in claims 24-30, both Barrett et al. and Patel et al. suggest that the release rate can be manipulated/tuned. Therefore, one skilled in the art would manipulate the concentration of the drug, thickness and porosity of the barrier layer, the amount of polymer in the core in order to achieve the desired release rate. Patel et al. teaches varying the ratios of these the hard and soft segments can alter the physical characteristics of the polyurethane the release rates of the actives can also be controlled by the hydrophilicity/hydrophobicity of the polyurethane polymers.
While the recitation “low-melting” is indefinite for the reasons set forth above, Patel et al. clearly teaches the soft segment is low-melting and that manipulation of the ratio of the hard and soft segments can alter the physical characteristics of the polyurethane. Patel et al. also teaches that the soft segments represent the section of the polymer that imparts the characteristics that determine the diffusivity of an active pharmaceutical ingredient through that polymer (paragraph 0023). The hydrophilicity can also be manipulated to control the release rate. These sections clearly suggest that manipulation of the amount of the soft segment would have been obvious and its manipulation customary to one skilled in the art in order to achieve the desired diffusivity/release of the drug.
Response to Arguments
Applicants’ arguments filed January 12 2026 have been fully considered but they are not persuasive.
Applicants argue (page 10) that the inventors surprisingly discovered that the use of crystalline EFdA anhydrate in TPU in the core of a melt-extruded implant that also contains a second TUP achieved EFdA loads as high as 60%. These API loads were higher than the up to 50% loads obtained in Barrett. This higher API load enables longer durations of activity.
Regarding Applicants’ arguments, even if this data were found persuasive, the data is not commensurate in scope with the instant claims. Firstly, the statements do not establish the expected effect. Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1371 (Fed. Cir. 2007) (holding that “evidence [of unexpected results] must fail because the record is devoid of any evidence of what the skilled artisan would have expected).
Secondly, the instant claims include the API in the core of between 1 and 60% by weight (see for example claim 1). Even a narrower limitation (see for example claims 4-5) include amounts which are not different from Barrett.
Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980) (Claims were directed to a process for removing corrosion at "elevated temperatures" using a certain ion exchange resin (with the exception of claim 8 which recited a temperature in excess of 100C). Appellant demonstrated unexpected results via comparative tests with the prior art ion exchange resin at 110C and 130C. The court affirmed the rejection of claims 1-7 and 9-10 because the term "elevated temperatures" encompassed temperatures as low as 60C where the prior art ion exchange resin was known to perform well. The rejection of claim 8, directed to a temperature in excess of 100C, was reversed.). See also In re Peterson, 315 F.3d 1325, 1329-31, 65 USPQ2d 1379, 1382-85 (Fed. Cir. 2003) (data showing improved alloy strength with the addition of 2% rhenium did not evidence unexpected results for the entire claimed range of about 1-3% rhenium); In re Grasselli, 713 F.2d 731, 741, 218 USPQ 769, 777 (Fed. Cir. 1983) (Claims were directed to certain catalysts containing an alkali metal. Evidence presented to rebut an obviousness rejection compared catalysts containing sodium with the prior art. The court held this evidence insufficient to rebut the prima facie case because experiments limited to sodium were not commensurate in scope with the claims.). Note: MPEP 716.02(d).
Applicants arguments with regards to the structure of the claimed API compared to Kohgo et al. are considered. This reference is not utilized in the rejection above. The examiner notes that newly cited Chang et al. appears to suggest a crystalline 4'-ethynyl-2-fluoro-2'-deoxyadenosine with a similar XRPD.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-7, 10-11, 13-22 and 24-30 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 12227536 in view of Barrett et al., Patel et al. and Kuzma et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
The instant application claims an implant drug delivery system comprising: (a) a core comprising a biocompatible nonerodible polymer comprising a thermoplastic poly(urethane) and crystalline 4'-ethynyl-2- fluoro-2'-deoxyadenosine anhydrate, wherein the 4'-ethynyl-2-fluoro-2'-deoxyadenosine anhydrate is present in the core between 1% and 60% by weight, and (b) a biocompatible nonerodible diffusional barrier comprising a polymer, wherein said diffusional barrier has a thickness between 50 pm and 300 pm, wherein said implant drug delivery system is adapted for subdermal implantation and 4'-ethynyl-2-fluoro-2'- deoxyadenosine anhydrate is continually released in vivo at a rate resulting in a plasma concentration of 4'-ethynyl-2-fluoro-2'-deoxyadenosine between 0.02 ng/mL and 300.0 ng/mL for a period of six months to thirty-six months.
As elected the diffusion barrier is poly(urethane).
The examiner notes that the specification indicates that 4'-ethynyl-2-fluoro-2'-deoxyadenosine is also known as islatravir (see page 9 of the instant specification).
Patent ‘536 claims crystalline anhydrous Form 1 of 2′ deoxy-4′-C-ethynyl-2-fluoroadenosine (EFdA) characterized by: (1) a powder x-ray diffraction pattern with peaks at diffraction angles degrees 2 theta (+/−) 0.2° of 4.48, 11.79, 14.70 and 25.81 in a powder x-ray diffraction obtained using Cu K alpha radiation, and/or (2) a solid state .sup.19F NMR spectrum comprising any two of the following peaks: −114.75, −117.09 and −118.92 ppm (claim 1). The crystalline anhydrous Form 1 of EFdA according to claim 1, characterized by a powder x-ray diffraction pattern with peaks at diffraction angles degrees 2 theta (+/−) 0.2° of 4.48, 11.79, 14.70, 25.81, 8.99, 12.39, 16.88, 27.42, 10.39, 15.51, 18.09 and 20.16 (claim 3). A solid dosage pharmaceutical composition comprising the crystalline anhydrate form is claimed (claims 10-11).
While patent ‘536 claims 4'-ethynyl-2- fluoro-2'-deoxyadenosine anhydrate with the same x-ray diffraction pattern and a solid pharmaceutical composition, patent ‘536 does not claim a core with a biocompatible nonerodable polymer and a biocompatible nonerodable diffusional barrier comprising a polymer. However, these deficiencies are cured by Barrett et al., Patel et al. and Kuzma et al.
Barrett et al. is directed to a drug delivery system for the delivery of antiviral agents. Claimed is an implant drug delivery system comprising a biocompatible nonerodible polymer and 4'-ethynyl-2-fluoro-2'-deoxyadenosine wherein said implant drug delivery system is implanted subdermally and 4'-ethynyl-2-fluoro-2'-deoxyadenosine is continually released in vivo at a rate resulting in a plasma concentration between 0.02 ng/mL and 300.0 ng/mL (claim 1). Claimed the 4'-ethynyl-2- fluoro-2'-deoxyadenosine plasma concentration is between 0.02 ng/mL and 30.0 ng/mL (claim 2) or the 4'-ethynyl-2- fluoro-2'-deoxyadenosine the plasma concentration is between 0.02 ng/mL and 8.0 ng/mL (claim 3). The biocompatible nonerodable polymer is ethylene vinyl acetate copolymer (claim 7-8). The system further comprises a diffusional barrier (claim 10) wherein specific diffusional barriers claimed is poly(urethane) (claim 12). The concentration of the 4'-ethynyl-2-fluoro-2'-deoxyadenosine in the biocompatible nonerodable polymer (i.e. core) is between 0.10% to 80% by weight (claim 14). Exemplified formulations contain 30-50 wt% 4'-ethynyl-2-fluoro-2'-deoxyadenosine and specifically 30, 35, 40, 45, and 50 wt% (table 2). The diffusional barrier is a coating that is permeable to the drug and placed over at least a portion of the device to further regulate the release. The diffusional barrier may be formed by coextrusion with the device (page 4, lines 18-23). Extrusion temperatures range from 110-140 °C (example 1). The delivery system can further comprise a radiopaque component in amounts from about 1% to 20% by weight. The radiopaque component can be an element such as barium sulphate (page 5, lines 12-16). The 4'-ethynyl-2-fluoro-2'-deoxyadenosine is released at therapeutic concentrations for a duration from between 3 months and 36 months (claim 18). The implant is capable of releasing 4'-ethynyl-2-fluoro-2'-deoxyadenosine over a period of 21 days, one month, six months, etc. at an average range of between 0.02-8.0 ng per day (page 9, lines 24-30).
Patel et al. is directed to an implantable device for drug delivery with reduce burst release. Claimed is an implantable device for delivery of a pharmaceutical substance comprising a core comprising a first polymeric material and a pharmaceutical substance and a shell comprising a second polymeric material and a porogen (claim 1). Porogens include soluble material such as sodium chloride (claim 10). Second polymeric material include polyurethane (claim 52). The core and shell can vary independently in thickness. Thickness of the shell can be from about 0.125 mm to about 4 mm (125 microns to 4000 microns) (paragraph 0086). The mean diameter of the porogens can be between about 1 micrometer and about 300 micrometers. In some embodiments, the mean diameter of the porogens is equal to the thickness of the shell (paragraph 0112). It is taught that surrounding the drug-containing core with a porogen-containing shell can reduce the burst release often observed with sustained release formations. Use of a porogen material having a narrow size distribution and the resulting narrow size distribution of the pores left in the shell after removal of the porogen allows for better control and tuning of the release rate of the drug from the core (paragraph 0007).
Kuzma et al. is directed to long term drug delivery devices with polyurethane-based polymers and their manufacture. Taught is the use of thermoplastic polyurethane-based polymers to create implantable drug delivery device (paragraph 0057). The thermoplastic polyurethanes can be processed through extrusion (paragraph 0058). Example 1 teaches tecophilic polyurethanes which are a aliphatic polyether-based thermoplastic polyurethane that can be formulated to different equilibrium water contents of up to 150% of the weight of dry resin. It is taught that from the standpoint of drug release form these materials, the release of a relatively hydrophilic API (active pharmaceutical) increases as the % EWC increases (paragraph 0030).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of patent ‘536, Barrett et al., Kuzma et al. and Patel et al. and utilize the drug delivery system of Barrett et al. One skilled in the art would have been motivated to utilize the drug delivery system of Barrett et al. as it is taught as a drug delivery system for 4'-ethynyl-2-fluoro-2'-deoxyadenosine. It would have been obvious with a reasonable expectation of success to use any known solid drug delivery system for 4'-ethynyl-2-fluoro-2'-deoxyadenosine.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of patent ‘536, Barrett et al., Kuzma et al. and Patel et al. and utilize a thermoplastic polyurethane core. One skilled in the art would have been motivated to utilize a thermoplastic polyurethane as Barrett et al. teaches the core material can be a polyurethane and Kuzma et al. teaches a thermoplastic polyurethane for a drug delivery implant. It would have been obvious to one of ordinary skill in the art to try known polyurethanes as a person with ordinary skill has good reason to pursue known options within his or her technical grasp. Note: MPEP 2141 KSR International CO. v. Teleflex Inc. 82 USPQ 2d 1385 (Supreme Court 2007).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of patent ‘536, Barrett et al., Kuzma et al. and Patel et al. and utilize a core with polyurethane and a polyurethane diffusional barrier with porogens such as sodium chloride (reading on instantly claimed soluble filler) and a thickness of 1 micrometer to about 300 micrometers. One skilled in the art would have been motivated to utilize this diffusional barrier in order to surround the drug-containing core with a porogen-containing shell to reduce the burst release often observed with sustained release formations as taught by Patel et al. Since the use of a porogen material having a narrow size distribution and the resulting narrow size distribution of the pores left in the shell after removal of the porogen allows for better control and tuning of the release rate of the drug from the core, one skilled in the art would have been motivated to utilize this particular diffusional barrier. Since Barrett et al. suggests a polyurethane diffusional layer there is a reasonable expectation of success.
Regarding the claimed thickness in claims 1, 15 and 24, Patel et al. teaches an overlapping range. 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). Note MPEP 2144.05. Furthermore, one skilled in the art would manipulate the shell thickness in order to achieve the desired release rate.
Regarding claims 2-7 and 22 Barrett et al. teaches an overlapping range for claimed concentration of 4'-ethynyl-2-fluoro-2'-deoxyadenosine anhydrate in the core and for the claimed plasma concentration and release time period. 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). Note MPEP 2144.05.
Regarding claim 14, Kuzma et al. teaches that the thermoplastic polyurethane that can be formulated to different equilibrium water contents of up to 150% and the precent water can control the release rate of the drug/API. Therefore, one skilled in the art would have been motivated to manipulate the structure of the thermoplastic polyurethane in order to achieve the desired water uptake and the desired release profile.
Regarding claims 17-18, Barrett et al. teaches co-extrusion and extrusion at a temperature of 110-140 °C which overlap the instant claims. 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). Note MPEP 2144.05.
Regarding claims 20-21, Barrett et al. teaches the inclusion of barium sulfate in the same concentration claimed.
Regarding the release rate in claims 24-30, both Barrett et al. and Patel et al. suggest that the release rate can be manipulated/tuned. Therefore, one skilled in the art would manipulate the concentration of the drug, thickness and porosity of the barrier layer, the amount of polymer in the core in order to achieve the desired release rate. Patel et al. teaches varying the ratios of these the hard and soft segments can alter the physical characteristics of the polyurethane the release rates of the actives can also be controlled by the hydrophilicity/hydrophobicity of the polyurethane polymers.
While the recitation “low-melting” is indefinite for the reasons set forth above, Patel et al. clearly teaches the soft segment is low-melting and that manipulation of the ratio of the hard and soft segments can alter the physical characteristics of the polyurethane. Patel et al. also teaches that the soft segments represent the section of the polymer that imparts the characteristics that determine the diffusivity of an active pharmaceutical ingredient through that polymer (paragraph 0023). The hydrophilicity can also be manipulated to control the release rate. These sections clearly suggest that manipulation of the amount of the soft segment would have been obvious and its manipulation customary to one skilled in the art in order to achieve the desired diffusivity/release of the drug.
Claims 1-7, 10-11, 13-22 and 24-30 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of copending Application No. 17920919 (USPGPUB No. 20230149296) in view of Kuzma et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The instant claims are set forth above.
Copending ‘919 claims an implant drug delivery system comprising:
(a) a core comprising a biocompatible nonerodible polymer and (i) islatravir anhydrate (aka 4'-ethynyl-2-fluoro-2'- deoxyadenosine anhydrate), which is present in the core between 10% to 50% by weight, and (ii) etonogestrel, which is present in the core between 25% to 50% by weight, and (b) a biocompatible nonerodible diffusional barrier comprising a polymer, wherein said diffusional barrier has a thickness between 50 pm and 300 µm, wherein said implant drug delivery system is implanted subdermally and (i) islatravir anhydrate is continually released in vivo at a rate resulting in a plasma concentration of islatravir between 0.02 ng/mL and 300.0 ng/mL for a period of six months to thirty-six months, and (ii) etonogestrel is continually released in vivo at a rate resulting in a plasma concentration of etonogestrel between 0.15ng/mL and 1.2 ng/mL a period of six months to thirty-six months (claim 1). The same or overlapping concentration of drug is claimed (claims 4-10). Core polymer of polyurethane is claimed (claim 11). A hydrophobic polymer with a soluble filler is claimed as the diffusional barrier. The same diffusional barrier is claimed (claims 13-14, 16). The same water uptake is claimed (claim 17). Same extrusion and temperature is claimed (claims 21-24). Radiopaque material in an amount from 1% and 20% by weight is claimed (claim 25). The same x-ray diffraction is claimed (claim 25). Same release rate is claimed (claim 1 and 30).
While Copending ‘919 claims the core polymer can be a polyurethane, copending ‘919 does not expressly claim a thermoplastic polyurethane. However, this deficiency is cured by Kuzma et al.
The teachings of Kuzma et al. are set forth above.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of copending ’919 and Kuzma et al. and utilize a thermoplastic polyurethane core. One skilled in the art would have been motivated to utilize a thermoplastic polyurethane as copending ‘919 teaches the core material can be a polyurethane and Kuzma et al. teaches a thermoplastic polyurethane for a drug delivery implant. It would have been obvious to one of ordinary skill in the art to try known polyurethanes as a person with ordinary skill has good reason to pursue known options within his or her technical grasp. Note: MPEP 2141 KSR International CO. v. Teleflex Inc. 82 USPQ 2d 1385 (Supreme Court 2007).
Regarding claim 14, Kuzma et al. teaches that the thermoplastic polyurethane that can be formulated to different equilibrium water contents of up to 150% and the precent water can control the release rate of the drug/API. Therefore, one skilled in the art would have been motivated to manipulate the structure of the thermoplastic polyurethane in order to achieve the desired water uptake and the desired release profile.
Regarding the release rate in claims 24-30, both Barrett et al. and Patel et al. suggest that the release rate can be manipulated/tuned. Therefore, one skilled in the art would manipulate the concentration of the drug, thickness and porosity of the barrier layer, the amount of polymer in the core in order to achieve the desired release rate. Patel et al. teaches varying the ratios of these the hard and soft segments can alter the physical characteristics of the polyurethane the release rates of the actives can also be controlled by the hydrophilicity/hydrophobicity of the polyurethane polymers.
While the recitation “low-melting” is indefinite for the reasons set forth above, Patel et al. clearly teaches the soft segment is low-melting and that manipulation of the ratio of the hard and soft segments can alter the physical characteristics of the polyurethane. Patel et al. also teaches that the soft segments represent the section of the polymer that imparts the characteristics that determine the diffusivity of an active pharmaceutical ingredient through that polymer (paragraph 0023). The hydrophilicity can also be manipulated to control the release rate. These sections clearly suggest that manipulation of the amount of the soft segment would have been obvious and its manipulation customary to one skilled in the art in order to achieve the desired diffusivity/release of the drug.
Therefore, the scopes of the copending claims and the instant application overlap and thus they are obvious variants of one another as both are directed to the same drug delivery system comprising the same drug, in an overlapping amount with either the same or overlapping release rate. The examiner notes that the instant claim language of comprising allows for other components such as the etonogestrel to be present.
Response to Arguments
Applicants argue that the amended claims are patentably distinct. However, Applicant respectfully requests that these rejections be held in abeyance until allowable subject matter.
Applicants’ arguments filed July 31 2025 have been fully considered but they are not persuasive.
Firstly, the argument do not clearly point out how the claims are patentably distinct. Secondly, Applicant(s) is/are reminded that a request to hold a rejection in abeyance is not a proper response to a rejection. Rather, a request to hold a matter in abeyance may only be made in response to an OBJECTION or REQUIREMENTS AS TO FORM (see MPEP 714.02 and CFR 1.111(b)).
Conclusion
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/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636