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 .
Status of the Claims
Claims 1 and 24-58 are pending. Claims 41-58 stand withdrawn without traverse.
Claims 1 and 24-40 are under current examination.
All rejections/objections not reiterated have been withdrawn.
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, 24-26, and 28-40 are rejected under 35 U.S.C. 103 as being unpatentable over Gaudriault (US 20120172454; publication date: 07/05/2012) in view of Lin et al. (Pharmaceutics 11, 413; publication date: 08/14/2019), and further in view of Washington et al. (US20180369160; publication date: 12/27/2018), and Mao et al. (J. Phys. Chem. B 2015, 119, 671-6480).
Gaudriault discloses a biodegradable drug delivery composition comprising a triblock copolymer containing a polyester and a polyethylene glycol and a diblock copolymer containing a polyester and an end-capped polyethylene glycol, as well as a pharmaceutically active principle (abstract) having the advantages of forming long acting formulations that reduce initial burst release of drug and modulate release rate over time (0008). The composition can be formulated to be injectable liquids at room temperature and create an in situ implant upon injection (0118). The composition contains (a) a biodegradable triblock copolymer having the formula:
Av-Bw-Ax
wherein A is a polyester and B is polyethylene glycol and v, w and x are the number of repeat units ranging from 4 to 1090 and v=x or v≠x; (b) a biodegradable diblock copolymer having the formula:
Cy-Az
wherein A is a polyester and C is an end-capped polyethylene glycol and y and z are the number of repeat units ranging from 3 to 237 or 7 to 371, wherein the ratio of the biodegradable triblock copolymer of (a) and the biodegradable CA diblock copolymer of (b) is 1:1 to 1:19 or 3:2 to 1:19 in said biodegradable drug composition; and (c) at least one pharmaceutically active principle (0010). More specifically, the triblock copolymer has the formula: PLAv-PEGw-PLAx and the biodegradable diblock copolymer has the formula: mPEGy-PLAz (mPEG is methoxy polyethylene glycol; 0014). The composition further comprises an organic solvent (0002); see also example compositions in which risperidone is formulated in dimethyl sulfoxide and various combinations of PLA-PEG-PLA and mPEG-PLA. The active principle is not limited and Gaudriault proposes formulating many broad categories of drug (0108). The triblock copolymer can be present in a range of 3 - 45 % w/w (claim 22), the diblock copolymer can be present in a range of 8 – 50 % w/w (claim 23), the active principle can be present in a range of 1 – 20 % w/w (claim 20), and the solvent can be present in a range of 40 – 74 % w/w (claim 28). The ranges in amount of each substance as well as in the number of each repeat unit taught by Gaudriault overlap with or embrace each of the corresponding ranges recited in the instant claims. See MPEP 2144.05(I).
Gaudriault does not disclose that the active principle is tacrolimus.
Lin teaches that tacrolimus is an immunosuppressive agent used to prevent rejection after allotransplantation but low aqueous solubility poses difficulties in formulating a dosage for injection (abstract). Lin solves this problem by formulating tacrolimus in an in situ biocompatible and biodegradable gel with adjustable drug release rate to maintain suitable plasma levels (abstract). The formulation is optimized by testing tacrolimus in several solvents known to dissolve tacrolimus in combination with the gel forming polymers (page 8, section 3.4).
Washington teaches that high systemic tacrolimus levels can cause life-threatening side effects, including diabetogenicity, nephrotoxicity, and neurotoxicity (0007).
Mao teaches PLA-PEG-PLA triblock copolymers in combination with PLA-PEG diblock copolymers can form gels in situ having highly tunable mechanical properties and sol-gel transition temperature (abstract, page 6478).
It would have been prima facie obvious to formulate tacrolimus as the active principle in Gaudriault’s composition. The skilled artisan would have been motivated to do so in order to provide steady release of tacrolimus with low burst to avoid toxicity in this highly tunable system that can be optimized to tailor drug release for different needs. The skilled artisan would have been further motivated to select Gaudriault’s polylactic acid/polyethylene glycol system in view of Mao’s teachings regarding ease with which the mechanical properties and gelation temperatures can be optimized in this type of system. The artisan of ordinary skill would have had a reasonable expectation of success because Gaudriault teaches their formulation is suitable for many different types of drugs and Mao provides insight into optimization of the properties of PLA-PEG-PLA/PLA-PEG hydrogel forming polymers.
With regard to the limitations of instant claims 24 and 25 on the values for v, x, w, y, and z, the ranges in these values recited in the instant claims fall within the ranges disclosed by Gaudriault for the number of repeat units in each polymer. Additionally, with regard to claim 24, Gaudriault teaches the size of the polyethylene glycol chain ranges from 200 Da to 12 kDa or 194 Da to 12 kDa (claim 6) and a lactic acid to ethylene oxide molar ratio of between 0.5 to 3.5 or 0.5 to 22.3 for the triblock copolymer 0022). The range in molecular weight of the PEG block and lactic acid/ethylene oxide ratio in the triblock copolymer embraces the amount recited in the instant claims (see MPEP 2144.05).
With regard to claim 26, Gaudriault teaches a range in lactic acid/ethylene oxide ratio of 2 to 6 or 0.8 to 13 for the diblock copolymer and that the mass of the end-capped polyethylene glycol (i.e. the molecular weight of the PEG repeat unit in the diblock copolymer) can range from 100 Da to 2 kDa. (0022, 0103; see MPEP 2144.05).
With regard to claim 28, Lin teaches that tacrolimus is soluble in DMSO (page 8, section 3.4) and Gaudriault teaches DMSO is a suitable solvent (claim 27), and uses DMSO as the solvent in example compositions. It would have been prima facie obvious to use DMSO as the solvent to formulate tacrolimus in Gaudriault’s invention because one having ordinary skill in the art would have reasonably expected it to suitably solubilize the drug and polymers.
With regard to claim 29, Gaudriault teaches a ratio of triblock to diblock copolymer of 3:2 to 1:19 (0002). This range embraces the ratio required by the instant claims (see MPEP 2144.05).
With regard to claims 30-32 and 38-40, as discussed above, the ranges in percent of triblock copolymer, diblock copolymer, active principle, and solvent overlap or embrace the ranges required by the instant claims (see MPEP 2144.05).
With regard to claim 33, which requires a generic excipient to be present, the examiner does not consider this limitation to patentably define over the cited prior art at least because Gaudriault discloses Mixtures of solvents can also be used (0035), in which case, one solvent falls within the scope of the term “solvent” recited in claim 1 and the other solvent(s) in the mixture fall within the scope of the term “excipient” required by instant claim 33 to be present in addition to the elements of claim 1.
With regard to claims 34-40, as noted above, Gaudriault teaches the size of the polyethylene glycol chain ranges from 200 Da to 12 kDa or 194 Da to 12 kDa (claim 6) and a lactic acid to ethylene oxide molar ratio of between 0.5 to 3.5 or 0.5 to 22.3 for the triblock copolymer and teaches a range in lactic acid/ethylene oxide ratio of 2 to 6 or 0.8 to 13 for the diblock copolymer and that the mass of the end-capped polyethylene glycol (i.e. the molecular weight of the PEG repeat unit in the diblock copolymer) can range from 100 Da to 2 kDa. (0022, 0103; see MPEP 2144.05).
Claim 27 is rejected under 35 U.S.C. 103 as being unpatentable over Gaudriault (US 20120172454; publication date: 07/05/2012) in view of Lin et al. (Pharmaceutics 11, 413; publication date: 08/14/2019), and further in view of Washington et al. (US20180369160; publication date: 12/27/2018), and Mao et al. (J. Phys. Chem. B 2015, 119, 671-6480) as applied to claims 1, 24-26, and 28-40 above, and further in view of Akoulitchev et al. (US 20160120853; publication date: 05/05/2016).
The relevant disclosures of Gaudriault, Lin, Washington, and Mao are set forth above. None of these references disclose tacrolimus monohydrate.
Akoulitchev discloses tacrolimus was available as tacrolimus monohydrate as of the instant filing date (0094).
It would have been prima facie obvious to use tacrolimus monohydrate as the form of tacrolimus in Gaudriault’s invention because one having ordinary skill would have recognized it as a suitable form of the drug (see MPEP 2144.07).
Response to Arguments
Applicant's arguments filed 07/16/2026 have been fully considered but they are not persuasive.
On page 12, Applicant argues Lin relates to a thermosensitive hydrogel system that is different from the in-situ-forming depot (ISFD) composition described in Gaudriault, Lin uses different excipients and a lower dose of tacrolimus vis a vis the instant claims and is accordingly not compatible with Gaudriault.
Insomuch as Applicant may be arguing that Lin is non-analogous art, the examiner points out that Lin is directed to tacrolimus formulations using polymers for sustained delivery and is therefore incontrovertibly in the same field of endeavor as both the instant invention and Gaudriault (PLA-PEG-PLA/mPEG-PLA polymer formulations to deliver difficult to formulate drugs). Regarding the fact that Lin teaches a somewhat different solution to the problem, Applicant is reminded that "The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain." In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983; see also MPEP 2123(I)). In the instant case, the examiner relied upon Lin merely for the background information that tacrolimus was known in the art to be problematic to formulate due to its solubility issues and had been previously solubilized in a gel system. The specific limitations regarding the components and quantities of substances in the claimed gel are addressed entirely by Gaudriault, who also teaches that a PLA-PEG-PLA/mPEG-PLA polymer formulation falling within the scope of the instant claims may be used to formulate drugs having poor water solubility in general to achieve sustained steady release and avoid toxic drug concentrations due to burst release. Applicant is reminded further that In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Regarding Applicant’s arguments on page 12 that Lin teaches advantages of the thermosensitive hydrogel system over PEG-PLA formulations and avoidance of toxic solvents, the existence of alternative solutions to tacrolimus solubility fails to negate the obviousness of the instant invention, as claimed. Simply because the prior art "discloses a multitude of effective combinations does not render any particular formulation less obvious." Merck & Co. v. Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed. Cir. 1989). The examiner notes that Gaudriault teaches a range of 40-74% w/w organic solvent, and therefore this quantity is considered suitable/compatible with drug delivery (prior art is presumed operable/enabling; see MPEP 2121(I)). Furthermore, it is noted that Applicants do not identify secondary consideration demonstrating criticality or anything unexpected about the combination of the claimed formulation and specific active agent, tacrolimus. Finally, the examiner points out that the section of Lin cited by Applicant as using below 1 wt% ethanol is in the context of tissue culture experiments and the concentration of ethanol was selected so as not to affect the tissue culture system (i.e. directly contacting cells growing on a tissue culture dish in cell culture media). This teaching has no bearing on what would have been toxic amounts of ethanol in another delivery system in a whole animal setting. Moreover, disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). "A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use." In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994) (see MPEP 2123(II)).
On page 13, Applicant argues that Lin would not have given a skilled artisan any expectation of success because Lin teaches that tacrolimus is highly hydrophobic and uses a much lower loading of tacrolimus than the presently-claimed subject-matter.
As discussed above, Lin was merely relied upon for the teaching that tacrolimus was known in the art as a drug that was difficult to formulate due to its hydrophobicity. The specifics of Lin’s formulation were not relied upon in the rationale supporting the obviousness conclusion. Contrary to Applicant’s assertion that one would have lacked expectation of success because Lin teaches that tacrolimus is highly hydrophobic, the skilled artisan would have had reasonable expectation of success formulating a hydrophobic agent in Gaudriault’s polymeric delivery system because (1) Gaudriault teaches that the drug itself is not limited and proposes formulating broad categories of drug, as noted in the rejection supra, and (2) the poor solubility of tacrolimus provides the motivation to attempt formulations such as Gaudriault’s that provide steady release and are taught to be suitable for many drugs. Further, with regard to expectation of success, Applicant is reminded that prior art documents are presumed enabling (MPEP 2121(I)) and as such, Gaudriault’s suggestion that the PLA-PEG-PLA/mPEG-PLA polymer formulation for low burst/steady release is not particularly limited in terms of what drug may be formulated must be taken at face value, absent evidence to the contrary.
On pages 13-14, Applicant argues that Mao discloses a composition that is materially different from a composition comprising copolymers and a large proportion of organic solvent and one of ordinary skill would have thought Mao’s teaching incompatible with Gaudriault; that Mao teaches it is only the properties of the hydrogel itself that are tunable; that one having ordinary skill would have thought this tunability highly specific to the specific aqueous system of Mao; that Mao is focused on a specific system using opposite stereochemical configurations of PLA that enable stereocomplex crystallization; that one having ordinary skill would not have been able to extrapolate anything from Mao to the system of Gaudriault; that Mao does not teach tunable properties to gel-to-drug release as such and provides no guidance on how to apply the findings to drug release generally or specifically to tacrolimus; and finally that the systems of Mao and Gaudriault operate on fundamentally different principles.
Regarding the relatedness of Gaudriault’s invention to that of Mao, the examiner points out that both are directed to in situ implant forming compositions comprised PLA-PEG-PLA/PEG-PLA polymers, thus the teachings of Mao (abstract: “in situ gelation”) are considered highly relevant to the teachings of Gaudriault (0008: “injectable in situ forming”). The examiner maintains that one having ordinary skill, e.g. a highly intelligent and well-educated individual having, for example, a Ph.D. in formulations or materials science, would have recognized the benefits of tuning the mechanical properties and/or sol-gel transition temperature for drug delivery. Moreover, as the system is so close in terms of identity of the two polymers, PEG-PLA/PEG-PLA, the artisan of ordinary skill would have recognized the applicability of Mao’s teachings, despite the fact that Gaudriault uses slightly different wording to describe the implant as “turn[ing] into solid implants when injected” (0008) and Mao describes “in situ gelation” (abstract). The mechanical properties of the polymer mixture change upon injection into a patient. The examiner respectfully disagrees with Applicant’s characterization of these two documents as describing systems that operate on fundamentally different principles for the foregoing reasons. Finally, in response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., stereochemical configurations of PLA) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). The claims place no limitation at all on the stereoconfigurations of the PLA and therefore read on any configuration, including the configurations affecting the properties discussed by Mao. The examiner also points out that Gaudriault makes no mention of the stereochemistry of the PLA segments other than in one example using DL-lactide. Therefore Gaudriault’s invention is not taught as limited or reliant on a particular stereochemistry.
On page 14, Applicant argues that Washington focuses on a device to be implanted; this is different than long-acting injectable compositions; that in Washinton tacrolimus is being used for neuroprotective/neuroregenerative applications; that Washington provides a different solution; and finally that no teaching that would have provided guidance to the arrive at the presently claimed subject matter, asserting that one would have been demotivated from using loading of 8 – 30% w/w tacrolimus.
In response, please see above regarding piecemeal analysis of references as well as the propriety of citing introduction/background teachings of prior art references. A prior art document may be relied upon for all it would have taught the artisan of ordinary skill. In this case, that Washington focuses on a different solution to tacrolimus toxicity does not negate the fact that tacrolimus had been recognized in the art as having potentially life threatening side effects. Washington’s background section was the only section of the disclosure relied upon in the rejection (see MPEP 2123 and see also Merck & Co. v. Biocraft Labs cited above). Moreover, the medical indication (neurological or otherwise) has no bearing on what had been recognized as of the instant effective filing date as toxic plasma concentrations of this drug. That is to say, the drug would not be less toxic if the purpose for its administration were other than for treating the neurological conditions discussed by Washington. Finally, the examiner points out that the prior art documents, Washington and Gaudriault, are directed to implants for sustained release and are therefore in the same field of endeavor, and more closely related than implied by the argument that Washinton teaches “a device to be implanted” vs. Gaudriault’s “long-acting injectable compositions”, noting that the injections of Gaudriault are placed within the body and release drug over an extended period of time much like Washington’s implant.
On pages 14-15, Applicant argues that the examiner has used impermissible hindsight to reject the claims.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
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, 24-26, and 28-40 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 9023897 in view of Lin et al. (Pharmaceutics 11, 413; publication date: 08/14/2019), and further in view of Washington et al. (US20180369160; publication date: 12/27/2018), and Mao et al. (J. Phys. Chem. B 2015, 119, 671-6480).
Inter alia, the claims of the 897 patent embrace a formulation comprising an active agent and a combination of a triblock copolymer with diblock copolymer in the presence of a solvent; wherein the triblock copolymer is a PLA-PEG-PLA copolymer and the diblock copolymer is an mPEG-PLA copolymer each having repeat units of PLA and PEG or mPEG that overlap in size with those recited in the instant claims either in terms of number of monomers, molecular weight, or mol ratios of the various blocks. More specifically, the cited patent embraces a biodegradable drug delivery composition comprising a triblock copolymer containing a polyester and a polyethylene glycol and a diblock copolymer containing a polyester and an end-capped polyethylene glycol, as well as a pharmaceutically active principle (abstract). The composition can be formulated to be injectable liquids at room temperature and create an in situ implant upon injection (0118). The composition contains (a) a biodegradable triblock copolymer having the formula:
Av-Bw-Ax
wherein A is a polyester and B is polyethylene glycol and v, w and x are the number of repeat units ranging from 4 to 1090 and v=x or v≠x; (b) a biodegradable diblock copolymer having the formula:
Cy-Az
wherein A is a polyester and C is an end-capped polyethylene glycol and y and z are the number of repeat units ranging from 3 to 237 or 7 to 371, wherein the ratio of the biodegradable triblock copolymer of (a) and the biodegradable CA diblock copolymer of (b) is 1:1 to 1:19 or 3:2 to 1:19 in said biodegradable drug composition; and (c) at least one pharmaceutically active principle (0010). More specifically, the triblock copolymer has the formula: PLAv-PEGw-PLAx and the biodegradable diblock copolymer has the formula: mPEGy-PLAz (mPEG is methoxy polyethylene glycol; 0014). The composition further comprises an organic solvent (0002); see also example compositions in which risperidone is formulated in dimethyl sulfoxide and various combinations of PLA-PEG-PLA and mPEG-PLA. The identity of the active principle is not limited and Gaudriault proposes formulating many broad categories of drug (0108).
The claims of the cited patent do not mention tacrolimus.
Lin teaches that tacrolimus is an immunosuppressive agent used to prevent rejection after allotransplantation but low aqueous solubility poses difficulties in formulating a dosage for injection (abstract). Lin solves this problem by formulating tacrolimus in an in situ biocompatible and biodegradable gel with adjustable drug release rate to maintain suitable plasma levels (abstract). The formulation is optimized by testing tacrolimus in several solvents known to dissolve tacrolimus in combination with the gel forming polymers (page 8, section 3.4).
Washington teaches that high systemic tacrolimus levels can cause life-threatening side effects, including diabetogenicity, nephrotoxicity, and neurotoxicity (0007).
Mao teaches PLA-PEG-PLA triblock copolymers in combination with PLA-PEG diblock copolymers can form gels in situ having highly tunable properties including mechanical and sol-gel transition temperature (abstract, page 6478).
It would have been prima facie obvious to formulate tacrolimus as the active principle in the composition embraced by the cited patents. The skilled artisan would have been motivated to do so in order to provide steady release of tacrolimus with low burst to avoid toxicity in this highly tunable system that can be optimized to tailor drug release for different needs. The skilled artisan would have been further motivated to select the polylactic acid/polyethylene glycol system in view of Mao’s teachings regarding ease with which the mechanical properties and gelation temperatures can be optimized in this system. The artisan of ordinary skill would have had a reasonable expectation of success because the claims of the cited patent any drug and Mao provides insight into optimization of the properties of PLA-PEG-PLA/PLA-PEG hydrogel forming polymers.
Claim 27 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 9023897 in view of Lin et al. (Pharmaceutics 11, 413; publication date: 08/14/2019), and further in view of Washington et al. (US20180369160; publication date: 12/27/2018), and Mao et al. (J. Phys. Chem. B 2015, 119, 671-6480) as applied to claims 1, 24-26, and 28-40 above, and further in view of Akoulitchev et al. (US 20160120853; publication date: 05/05/2016).
The relevant limitations of the cited patent and disclosures of Lin, Washington, and Mao are set forth above. None of these references disclose tacrolimus monohydrate.
Akoulitchev discloses tacrolimus was available as tacrolimus monohydrate as of the instant filing date (0094).
It would have been prima facie obvious to use tacrolimus monohydrate as the form of tacrolimus in invention of the cited patent because one having ordinary skill would have recognized it as a suitable form of the drug (see MPEP 2144.07).
Claims 1, 24-26, and 28-40 are rejected on the ground of nonstatutory double patenting as being unpatentable over
claims 1-34 of U.S. Patent No. 11612563;
claims 1-29 of U.S. Patent No. 11801217;
claims 22 and 24 of U.S. Patent No. 12128132; and
claims 30 of U.S. Patent No. 12383493
in view of Gaudriault (US 20120172454; publication date: 07/05/2012) and further in view of Lin et al. (Pharmaceutics 11, 413; publication date: 08/14/2019), Washington et al. (US20180369160; publication date: 12/27/2018), Mao et al. (J. Phys. Chem. B 2015, 119, 671-6480).
Inter alia, the claims of the cited patents embrace a formulation comprising an active agent and a combination of a triblock copolymer with diblock copolymer in the presence of a solvent; wherein the triblock copolymer is a PLA-PEG-PLA copolymer and the diblock copolymer is an mPEG-PLA copolymer each having repeat units of PLA and PEG or mPEG that overlap in size with those recited in the instant claims either in terms of number of monomers, molecular weight, or mol ratios of the various blocks.
The cited patents do not require the drug to be tacrolimus; however, the examiner considers the invention in each case to be the formulation containing the two copolymers and a solvent, regardless of the identity of the drug in view of Gaudriault:
Gaudriault discloses a biodegradable drug delivery composition comprising a triblock copolymer containing a polyester and a polyethylene glycol and a diblock copolymer containing a polyester and an end-capped polyethylene glycol, as well as a pharmaceutically active principle (abstract). The composition can be formulated to be injectable liquids at room temperature and create an in situ implant upon injection (0118). The composition contains (a) a biodegradable triblock copolymer having the formula:
Av-Bw-Ax
wherein A is a polyester and B is polyethylene glycol and v, w and x are the number of repeat units ranging from 4 to 1090 and v=x or v≠x; (b) a biodegradable diblock copolymer having the formula:
Cy-Az
wherein A is a polyester and C is an end-capped polyethylene glycol and y and z are the number of repeat units ranging from 3 to 237 or 7 to 371, wherein the ratio of the biodegradable triblock copolymer of (a) and the biodegradable CA diblock copolymer of (b) is 1:1 to 1:19 or 3:2 to 1:19 in said biodegradable drug composition; and (c) at least one pharmaceutically active principle (0010). More specifically, the triblock copolymer has the formula: PLAv-PEGw-PLAx and the biodegradable diblock copolymer has the formula: mPEGy-PLAz (mPEG is methoxy polyethylene glycol; 0014). The composition further comprises an organic solvent (0002); see also example compositions in which risperidone is formulated in dimethyl sulfoxide and various combinations of PLA-PEG-PLA and mPEG-PLA.
Gaudriault teaches that in such systems, the identity of the active principle is not limited and Gaudriault proposes formulating many broad categories of drug (0108). Gaudriault discloses further that the system has the advantages of forming long acting formulations that reduce initial burst release of drug and modulate release rate over time (0008).
Lin teaches that tacrolimus is an immunosuppressive agent used to prevent rejection after allotransplantation but low aqueous solubility poses difficulties in formulating a dosage for injection (abstract). Lin solves this problem by formulating tacrolimus in an in situ biocompatible and biodegradable gel with adjustable drug release rate to maintain suitable plasma levels (abstract). The formulation is optimized by testing tacrolimus in several solvents known to dissolve tacrolimus in combination with the gel forming polymers (page 8, section 3.4).
Washington teaches that high systemic tacrolimus levels can cause life-threatening side effects, including diabetogenicity, nephrotoxicity, and neurotoxicity (0007).
Mao teaches PLA-PEG-PLA triblock copolymers in combination with PLA-PEG diblock copolymers can form gels in situ having highly tunable properties including mechanical and sol-gel transition temperature (abstract, page 6478).
It would have been prima facie obvious to formulate tacrolimus as the active principle in the composition embraced by the cited patents. The skilled artisan would have been motivated to do so in order to provide steady release of tacrolimus with low burst to avoid toxicity in this highly tunable system that can be optimized to tailor drug release for different needs. The skilled artisan would have been further motivated to select the polylactic acid/polyethylene glycol system in view of Mao’s teachings regarding ease with which the mechanical properties and gelation temperatures can be optimized in this system. The artisan of ordinary skill would have had a reasonable expectation of success because Gaudriault teaches this type of formulation is suitable for many different types of drugs and Mao provides insight into optimization of the properties of PLA-PEG-PLA/PLA-PEG hydrogel forming polymers.
Claim 27 is rejected on the ground of nonstatutory double patenting as being unpatentable over
claims 1-34 of U.S. Patent No. 11612563;
claims 1-29 of U.S. Patent No. 11801217;
claims 22 and 24 of U.S. Patent No. 12128132; and
claims 30 of U.S. Patent No. 12383493
in view of Gaudriault (US 20120172454; publication date: 07/05/2012) and further in view of Lin et al. (Pharmaceutics 11, 413; publication date: 08/14/2019), Washington et al. (US20180369160; publication date: 12/27/2018), Mao et al. (J. Phys. Chem. B 2015, 119, 671-6480) as applied to claims 1, 24-26, and 28-40 above, and further in view of Akoulitchev et al. (US 20160120853; publication date: 05/05/2016).
The relevant limitations of the cited patents and disclosures of Gaudriault, Lin, Washington, and Mao are set forth above. None of these references disclose tacrolimus monohydrate.
Akoulitchev discloses tacrolimus was available as tacrolimus monohydrate as of the instant filing date (0094).
It would have been prima facie obvious to use tacrolimus monohydrate as the form of tacrolimus in invention of the cited patents because one having ordinary skill would have recognized it as a suitable form of the drug (see MPEP 2144.07).
Claims 1, 24-26, and 28-40 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over
claims 1-45 of copending Application No. 18283350;
claims 1-43 of copending Application No. 18409158;
claims 1-20 of copending Application No. 18557882;
claims 1, 2, 5, 8, 11, 14-16, 18-20, 23-25, 28, 43-45, 50, 51, 55, 57, 61, 63-65, 78, 82, 83, 91, 92, and 95 of copending Application No. 19146298; and
claims 1-29 of copending Application No. 19205563
in view of in view of Gaudriault (US 20120172454; publication date: 07/05/2012) and further in view of Lin et al. (Pharmaceutics 11, 413; publication date: 08/14/2019), Washington et al. (US20180369160; publication date: 12/27/2018), Mao et al. (J. Phys. Chem. B 2015, 119, 671-6480).
Inter alia, the claims of the cited applications embrace a formulation comprising an active agent and a combination of a triblock copolymer with diblock copolymer in the presence of a solvent; wherein the triblock copolymer is a PLA-PEG-PLA copolymer and the diblock copolymer is an mPEG-PLA copolymer each having repeat units of PLA and PEG or mPEG that overlap in size with those recited in the instant claims either in terms of number of monomers, molecular weight, or mol ratios of the various blocks.
The cited applications do not require the drug to be tacrolimus; however, the examiner considers the invention in each case to be the formulation containing the two copolymers and a solvent, regardless of the identity of the drug in view of Gaudriault:
Gaudriault discloses a biodegradable drug delivery composition comprising a triblock copolymer containing a polyester and a polyethylene glycol and a diblock copolymer containing a polyester and an end-capped polyethylene glycol, as well as a pharmaceutically active principle (abstract). The composition can be formulated to be injectable liquids at room temperature and create an in situ implant upon injection (0118). The composition contains (a) a biodegradable triblock copolymer having the formula:
Av-Bw-Ax
wherein A is a polyester and B is polyethylene glycol and v, w and x are the number of repeat units ranging from 4 to 1090 and v=x or v≠x; (b) a biodegradable diblock copolymer having the formula:
Cy-Az
wherein A is a polyester and C is an end-capped polyethylene glycol and y and z are the number of repeat units ranging from 3 to 237 or 7 to 371, wherein the ratio of the biodegradable triblock copolymer of (a) and the biodegradable CA diblock copolymer of (b) is 1:1 to 1:19 or 3:2 to 1:19 in said biodegradable drug composition; and (c) at least one pharmaceutically active principle (0010). More specifically, the triblock copolymer has the formula: PLAv-PEGw-PLAx and the biodegradable diblock copolymer has the formula: mPEGy-PLAz (mPEG is methoxy polyethylene glycol; 0014). The composition further comprises an organic solvent (0002); see also example compositions in which risperidone is formulated in dimethyl sulfoxide and various combinations of PLA-PEG-PLA and mPEG-PLA.
Gaudriault teaches that in such systems, the identity of the active principle is not limited and Gaudriault proposes formulating many broad categories of drug (0108). Gaudriault discloses further that the system has the advantages of forming long acting formulations that reduce initial burst release of drug and modulate release rate over time (0008).
Lin teaches that tacrolimus is an immunosuppressive agent used to prevent rejection after allotransplantation but low aqueous solubility poses difficulties in formulating a dosage for injection (abstract). Lin solves this problem by formulating tacrolimus in an in situ biocompatible and biodegradable gel with adjustable drug release rate to maintain suitable plasma levels (abstract). The formulation is optimized by testing tacrolimus in several solvents known to dissolve tacrolimus in combination with the gel forming polymers (page 8, section 3.4).
Washington teaches that high systemic tacrolimus levels can cause life-threatening side effects, including diabetogenicity, nephrotoxicity, and neurotoxicity (0007).
Mao teaches PLA-PEG-PLA triblock copolymers in combination with PLA-PEG diblock copolymers can form gels in situ having highly tunable properties including mechanical and sol-gel transition temperature (abstract, page 6478).
It would have been prima facie obvious to formulate tacrolimus as the active principle in the composition embraced by the cited applications. The skilled artisan would have been motivated to do so in order to provide steady release of tacrolimus with low burst to avoid toxicity in this highly tunable system that can be optimized to tailor drug release for different needs. The skilled artisan would have been further motivated to select the polylactic acid/polyethylene glycol system in view of Mao’s teachings regarding ease with which the mechanical properties and gelation temperatures can be optimized in this system. The artisan of ordinary skill would have had a reasonable expectation of success because Gaudriault teaches this type of formulation is suitable for many different types of drugs and Mao provides insight into optimization of the properties of PLA-PEG-PLA/PLA-PEG hydrogel forming polymers.
This is a provisional nonstatutory double patenting rejection.
Claim 27 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over
claims 1-45 of copending Application No. 18283350;
claims 1-43 of copending Application No. 18409158;
claims 1-20 of copending Application No. 18557882;
claims 1, 2, 5, 8, 11, 14-16, 18-20, 23-25, 28, 43-45, 50, 51, 55, 57, 61, 63-65, 78, 82, 83, 91, 92, and 95 of copending Application No. 19146298; and
claims 1-29 of copending Application No. 19205563
in view of in view of Gaudriault (US 20120172454; publication date: 07/05/2012) and further in view of Lin et al. (Pharmaceutics 11, 413; publication date: 08/14/2019), Washington et al. (US20180369160; publication date: 12/27/2018), Mao et al. (J. Phys. Chem. B 2015, 119, 671-6480) as applied to claims 1, 24-26, and 28-40 above, and further in view of Akoulitchev et al. (US 20160120853; publication date: 05/05/2016).
The relevant limitations of the cited patents and disclosures of Gaudriault, Lin, Washington, and Mao are set forth above. None of these references disclose tacrolimus monohydrate.
Akoulitchev discloses tacrolimus was available as tacrolimus monohydrate as of the instant filing date (0094).
It would have been prima facie obvious to use tacrolimus monohydrate as the form of tacrolimus in invention of the cited applications because one having ordinary skill would have recognized it as a suitable form of the drug (see MPEP 2144.07).
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed 07/16/2026 have been fully considered but they are not persuasive.
On pages 16-17 of the remarks, in traversal of the non-statutory double patenting rejections, Applicant argues that the cited patents and applications are directed to formulations of drugs other than tacrolimus.
This is not persuasive because the invention appears to be the drug delivery system, rather than the specific drug being delivered. The examiner’s position is further supported by Gaudriault’s teaching that the identity of the drug is not limited in very similar drug delivery systems.
On page 17, Applicant’s argument that one having ordinary skill would not have been motivated to combine Gaudriault, Lin, Washington, Mao, and Akoulitchev with the cited copending applications or patents is not persuasive because it does not address the specific reasoning delineated in the rejections.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/KATHERINE PEEBLES/ Primary Examiner, Art Unit 1617
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