DETAILED ACTION
Claims 1, 3-10, 13, 17-19 and 21-33 are currently pending. Claims 1, 3-10, 13, 17-19, 21-28 and 30-33 are currently under examination.
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 .
Information Disclosure Statement
Applicant’s Informational Disclosure Statement, filed on 12/02/2025 has been considered. Please refer to Applicant’s copy of the 1449 submitted herein.
Withdrawn Rejections
The rejection of claims 1-28 and 30 under 112(b) is withdrawn as a result of Applicant clarifying the structure of the claim and intended use of the implant.
The rejection of claim(s) 1-16, 20-28 and 30 under 35 U.S.C. 103 as being unpatentable over WO 2017/196697 in view of US 2016/0000797 and US 2015/0231079 is withdrawn as a result of Applicant amended the independent claims to require a hydrophobic and aliphatic thermoplastic polyurethane core and a hydrophilic thermoplastic polyurethane diffusional barrier which the combination of references does not teach.
Examiner’s Note
Applicant's amendments and arguments filed 12/02/2025 are acknowledged and have been fully considered. The Examiner has re-weighed all the evidence of record. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application. In the Applicant’s response, filed 12/02/2025, it is noted that claims 1, 3, 13, 17, 25 and 30 have been amended and claims 31-33 are newly added. No new matter or claims have been added.
New Rejections:
The following rejections are newly applied based on Applicant’s claim amendments.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 3-10, 17, 21-28 and 30-33 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO 2017/196697 (previously applied) in view of US 2015/0231079 (previously applied), US 2015/0136143 and US 2012/0231061 (IDS dated 12/02/2025).
Regarding claims 1, 27, 30, 32-33, the limitation of an implant drug delivery system comprising (a) a core comprising a biocompatible nonerodable polymer comprising a hydrophobic and aliphatic thermoplastic polyurethane (TPU) and (i) islatravir, which is present in the core between 10 to 50% by weight and (b) a biocompatible nonerodable diffusional barrier comprising a polymer, wherein the polymer comprises a TPU, wherein said diffusional barrier has a thickness between 50 um and 300 um is met by the ‘697 publication teaching long-acting delivery of antiviral drugs wherein the compositions are implantable drug delivery systems useful for the treatment or prevention of human immunodeficiency virus (HIV) infection (abstract). Implant drug delivery systems comprising a biocompatible nonerodable polymer and 4’-ethynyl-2-fluoro-2’-deoxyadenosine wherein said implant drug delivery system is implanted sub dermally and is released in vivo at a rate resulting in plasma concentration between 0.01 ng/mL and 3000 ng/mL (page 3, lines 8-20). The polymer is taught to be non-erodible (page 3, lines 30-35) and include poly(urethane (page 4, lines 1-5, 10-15). The diffusional barrier includes poly(urethane wherein the polymer is hydrophobic (page 4, lines 20-30). The antiviral is present at 20-60% by weight and is 4’-ethynyl-2-fluoro-2’-deoxyadenosine (page 8, lines 1-10). The drug is released at a rate of 0.02 to 8 ng per day for one to 36 months (page 9, lines 24-30). The 4’-ethynyl-2-fluoro-2’-deoxyadenosine is islatravir per the instant specification page 9). The diffusion polymer is taught to be polyurethane (page 1, lines 24-35).
Regarding claims 1 and 3-7, the limitation of wherein the islatravir plasma concentration is between 0.02ng/ml and 30.0 ng/ml, 0.02ng/ml and 8.0 ng/ml and 15, 20, 30 and 35% by weight is met by the antiviral is present at about 20-60% by weight and is 4’-ethynyl-2-fluoro-2’-deoxyadenosine (page 8, lines 1-10). The drug is released at a rate of 0.02 to 8 ng per day for 36 months (page 9, lines 24-30). As MPEP 2144.05 recites “where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine optimization”.
Regarding claims 11-12, the limitation of wherein the biocompatible nonerodable polymer in the core is polyurethane is met by the ‘697 publication teaching the biocompatible nonerodable polymer is polyurethane (page 3-4).
Regarding claim 21-24, the limitation of wherein the core and the biocompatible nonerodable diffusional carrier are prepared by co-extrusion and the co-extrusion is carried out at a temperature between 130 and 190 degrees C is met by the ‘697 publication teaching extrusion of twin extrusion at temperatures of 100 to 140 degrees C (Example 1) wherein the device may be formed by coextrusion (page 4, lines 15-25). MPEP 2113 - “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985).
Regarding claim 26, the limitation of comprising between 1% and 20% y weight of a radiopaque material is met by the ‘697 publication teaching 1-30% by weight of radiopaque material (page 5, lines 15-25).
The ‘697 publication does not specifically teach islatravir anhydrate (claim 1).
The ‘697 publication does not specifically teach etonogestrel, which is present in the core between 25% to 50% by weight (claim 1).
The ‘697 publication does not specifically teach the diffusions barrier is hydrophilic TPU (claim 1).
The ’079 publication teaches pharmaceutical antiretroviral composition comprising at least one integrase inhibitor or anhydrate thereof and at least one antiretroviral or anti-HIV agent or anhydrate thereof (abstract). The term “integrase inhibitor (for example dolutegravir, elvitegravir or raltegravir) or “anti-HIV agent” and “Anti-retroviral agents) are taught to be used in pharmaceutically acceptable anhydrate form ([0041]-[0046]).
The ‘143 publication teaches intravaginal drug delivery devices for administration of dapivirine in combination with a contraceptive to a human. Blocking DNS polymerization by an HIV reverse transcriptase enzyme and method of preventing HIV infection in a female human and method of preventing unintended pregnancy in a human female are taught (abstract). The device is taught to have a core loaded substance and an outer sheath. The polymeric materials are taught to include hydrophobic materials such as polyurethane [0008]. Etonorgestrel is taught [0010]. The contraceptive is taught to be released at between 35 and 70 ug/day for about 53 days [0020]. A core sheath configuration is taught [0024]. Dapivirine is taught to be used for prevention or treatment of a retroviral infection [0115]. Those of skill in the prevention and/or treatment of HIV and the prevention of pregnancy could determine appropriate therapeutically effective amount of prophylactically effective amount from the data presented here [0182].
The ‘061 publication teaches polyurethane-based polymer as drug delivery device to delivery biologically active compound at a constant rate for an extended period of time. The device is biocompatible and biostable and useful as an implant in patients (abstract). The drug delivery device for the controlled release of at least one active agent over an extended period of time to produce local or systemic pharmaceutically effects comprising a polyurethane base polymer comprising one or more functional groups selected form the group consisting of hydrophilic pendent groups and hydrophobic pendent groups and mixture thereof. The functional groups determine the degree in which the polymer is hydrophobic or hydrophilic and a solid drug formation and a carrier in the core [0005]. Tecophilic hydrophilic polyurethane is taught [0030] which has a water content from 5-43% [0030].
It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to use etonogestrel in the implant taught by the ‘697 publication because the ‘143 publication that it is known to use a contraceptive such as etonogestrel in combination with an antiviral agent and the ‘697 publication is directed to an implant comprising antiviral agents. One of ordinary skill in the art before the filing date of the claimed invention would be motivated to include etonogestrel in the implant of the ‘697 publication because the ‘143 publication teaches the desire to prevent HIV infection and unintended pregnancy in females [005]. One of ordinary skill in the art before the filing date of the claimed invention would have a reasonable expectation of success as the ‘697 publication teaches an antiviral to treat HIV used in an implant comprising a polyurethane core and polyurethane shell and the ‘143 publication teaches the combination of an antiviral and contraceptive to be used in a medical device comprising polyurethane and a core shell structure.
That being said and in lieu of objective evidence of unexpected results, the dosage and release rate can be viewed as a variable which achieves the recognized result of successfully treating a specific patient. The optimum or workable range of dosing can be accordingly characterized as routine optimization and experimentation (see MPEP 2144.05 (II)B). “[Discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.” In re Boesch, 617 F.2d 272, 276 (CCPA 1980). Appellants provide no evidence of any secondary consideration such as unexpected results that would render the optimized amounts of dosage nonobvious and the ’143 publication teaches the active agent amount to be an optimizable parameter.
It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to use tecophilic polyurethane for the diffusion layer as taught by the ‘697 publication because the ‘697 publication teaches the use of polyurethane diffusion polymers and the ‘061 publication teaches the specific tecophilic polyurethane to be used in an implantable device. One of ordinary skill in the art would be motivated to use the tecophilic polymer as the polyurethane polymer taught by the ‘697 publication because the ‘061 publication teaches the hydrophilic and hydrophobic functional groups being used to control the release of the active agents.
It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to use the 4’-ethynyl-2-fluoro-2’-deoxyadenosine nucleoside reverse transcriptase inhibitor as taught by the ‘697 publication in anhydrate form as the ‘079 publication teaches anhydrates to be a known form to be used of integrase inhibitors in pharmaceutical compositions. One of ordinary skill in the art before the effective filing date of the claimed invention would have a reasonable expectation of success as the ‘079 publication teaches known forms of integrase inhibitor drugs to be used in pharmaceutical composition and the ‘697 publication teaches specific integrase inhibitor to be used in a pharmaceutical composition.
Regarding the specific x-ray diffraction pattern, the ‘079 publication teaches anhydrate form of anti-viral drug, which would meet the x-ray powder diffraction absent factual evidence to the contrary. The U.S. Patent Office is not equipped with analytical instruments to test prior art compositions for the infinite number of ways that a subsequent Applicant may present previously unmeasured characteristics. When as here, the prior art appears to contain the exact same ingredients and Applicant’s own disclose supports the suitability of the prior composition as the inventive composition component, the burden is property shifted to Applicant to show otherwise.
Claim(s) 13 and 18-19 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO 2017/196697, US 2015/0231079, US 2015/0136143 and US 2012/0231061 as applied to claims 1, 3-10, 17, 21-28 and 30-33 above, and further in view of US 5,344,411.
As mentioned in the above 103 rejection, all of the limitations of claims 1, 3-10, 17, 21-28 and 30-33 are taught by the combination of the ‘697 publication, the ‘079 publication, the ‘143 publication and the ‘061 publication.
The combination of references does not specifically teach wherein the diffusional barrier further comprises an additive selected form the group consisting of polyethylene glycol, citric acid and poloxamer (claim 18).
The combination of references does not specifically recite the diffusional barrier has a thickness between 100 um and 200 um (claim 19).
The ‘411 patent teaches anti-infective coating for a catheter or other medical device. The coating is insoluble in the biological medium and bound to the surface of the catheter. The matrix is taught to have sustained release (abstract). The composition of the polymer coating may alter the release of iodine from the polymer matrixes. The coating may further contain additives such as organic salts, complexing molecules including a hydrophilic additive such as polyethylene glycol to increase the release rate since it increases the water penetration into the polymer coating (column 11, lines 40-67). Coatings are taught to be from 0.01 and 1.0 mm in thickness wherein the coatings may be formed form any suitable method (column 9, lines 5-25). The release is a function of and varies according to the thickness, concentration, chemical composition and solubility of the polymer from which the coating (column 11, lines 1-10). The composition is for treatment of HIV virus (Example 7).
It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to use polyethylene glycol as taught by the ‘411 patent in the barrier layer taught by the ‘697 publication because the ‘411 publication teaches the use of hydrophilic polymers such as PEG to be used in coating layers to control drug release. One of ordinary skill in art would have a prima facie obvious expectation of success as the ‘697 publication teaches implantable drug delivery devices comprising barrier layers to control the rate of release and the ‘411 publication teaches a coating layer containing PEG to control the rate of release of an active agent. It would have been prima facie obvious to one of ordinary skill in the art to use the coating thickness aught by the ‘411 publication for the diffusion layer of the ‘697 publication and optimize as the ‘697 publication teaches the diffusion layer to control the drug release rate and the ‘411 publication teaches known coating thickness wherein the thickness is taught to control the drug release. As MPEP 2144.05 recites “where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine optimization”.
Response to Arguments:
Applicant’s arguments have been fully considered and are not deemed to be persuasive.
Applicant argues the combination of references fail to teach or suggest an implant device containing islatravir anhydrate. The ‘079 publication (Malhotra) fail to teach or suggest an anhydrate of a nucleoside reverse transcriptase agent let alone specifically islatravir. The mention of anhydrates is a mention in a laundry list of acceptable forms of anti-HIV agents without pointing to any benefits of pursuing an anhydrate specifically.
In response, it would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to use the 4’-ethynyl-2-fluoro-2’-deoxyadenosine nucleoside reverse transcriptase inhibitor as taught by the ‘697 publication in anhydrate form as the ‘079 publication teaches anhydrates to be a known form to be used of integrase inhibitors in pharmaceutical compositions. One of ordinary skill in the art before the effective filing date of the claimed invention would have a reasonable expectation of success as the ‘079 publication teaches known forms of integrase inhibitor drugs to be used in pharmaceutical composition and the ‘697 publication teaches specific integrase inhibitor to be used in a pharmaceutical composition. Thus the anhydrate form was known in the prior art. Applicant has provided no unexpected results regarding the use of the anhydrate form.
Applicant argues the unexpected finding that islatravir and ENG are able to dissolve and diffuse through multiple types of TPU polymer synchronously. Islatravir is highly soluble in water while ENG is insoluble in water. A person skilled in the art recognize the impediments in simultaneously co-administration of a highly soluble active agent and an insoluble active agent form a single medical device. Table 4 demonstrates significantly different logP and pKa values. Synchronous long-term co-delivery of desired doses of islatravir ad ENG form a single implant device was an art-recognized challenge. None of the provided references even consider how to make a polymeric matrix implant system containing islatravir and a second hydrophobic agent. By design inventors have disclosed a hydrophobic core with both ENG and islatravir anhydrate are dissolved and outer diffusional barrier comprising hydrophilic TPU polymer they could synchronous co-delivery of these agents. Example 4 demonstrates release is achievable and tunable.
In response, Applicant point to Table 4 in the instant specification which demonstrates the relate release rate is lower for devices containing a WU diffusion barrier with 5% and 10% water uptake compared to those with only a TPU core. The ‘697 publication teaches an antiviral to treat HIV used in an implant comprising a polyurethane core and polyurethane shell and the ‘143 publication teaches the combination of an antiviral and contraceptive to be used in a medical device comprising polyurethane and a core shell structure. Thus the use of a polyurethane sheath/diffusion layer polymer over the drug containing core for the release of both islatravir and etonogestrel was known at the time of the invention. Additionally, the ‘061 publication teaches techophilic polymers which contain an optimizable water update for the controlled release of an implantable active agent wherein the hydrophobicity and hydrophilicity is known to control the drug release rate ([0030], [0016]), thus the use of hydrophilic polyurethane polymer to release the active agents is prima facie obvious and the reduced release rate is not unexpected in addition of the sheath/diffusion layer. Regarding the release of multiple agents with different hydrophilicity/hydrophobicity from a single device, the ‘143 publication teaches the desire to co-administer an HIV preventing/treating active agent and a contraceptive from a single polyurethane decide which contains a polyurethane coating, thus it was not unexpected to combine the two types of drugs in a single polyurethane implant with a polyurethane sheath.
Conclusion
No claims are allowed.
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.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LYNDSEY MARIE BECKHARDT whose telephone number is (571)270-7676. The examiner can normally be reached Monday-Thursday 9am to 4pm and Friday 9am to 2pm.
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/LYNDSEY M BECKHARDT/Examiner, Art Unit 1613
/BRIAN-YONG S KWON/Supervisory Patent Examiner, Art Unit 1613