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 .
Claim Status
Claim 20 is cancelled.
Claims 1-19 are pending.
Claims 13-15, 18 and 19 are withdrawn.
Claims 1-12, 16 and 17 are presented for examination on the merits.
Priority
Applicant’s amendment finds support in the provisional applications.
Withdrawn rejections
Applicant's amendments and arguments filed 5/19/26 are acknowledged and have been fully considered. The Examiner has re-weighed all the evidence of record. Any rejection and/or objection not specifically addressed below is herein withdrawn. Claims 1-12, 16 and 17 were rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. Claim(s) 1, 3, 6-10 and 12 were rejected under 35 U.S.C. 102(a)(2) as being anticipated by Minrovic et al. (WO2022198167 published September 22, 2022; IDS filed 6/28/24). Claims 1-12, 16 and 17 were rejected under 35 U.S.C. 103 as being obvious over Minrovic et al. (WO2022198167). Applicant’s amendments and arguments are persuasive. Applicant’s amendments have removed Minrovic et al. (WO2022198167) as prior art.
Claim Objections
Claim 1 is objected to because of the following informalities: applicant deleted “poly(ortho ester)”, which provides clarity for the acronym “POE”. Appropriate correction is required.
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.
Claims 1-12, 16 and 17 are rejected under 35 U.S.C. 103 as being obvious over Kim (US20200261878) and Zale et al. (US7799345) and Bai et al. (Journal of Applied Polymer Science, Vol. 80, 1630–1642 (2001)).
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103, the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103.
Applicant claims, for example:
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Level of Ordinary Skill in the Art
(MPEP 2141.03)
MPEP 2141.03 (I) states: “The “hypothetical ‘person having ordinary skill in the art’ to which the claimed subject matter pertains would, of necessity have the capability of understanding the scientific and engineering principles applicable to the pertinent art.” Ex parte Hiyamizu, 10 USPQ2d 1393, 1394 (Bd. Pat. App. & Inter. 1988). The level of skill is that of a pharmaceutical formulation research scientist, as is the case here, then one can assume comfortably that such an educated artisan will draw conventional ideas from pharmaceutical formulation techniques, materials, active agents and their derivatives and procedures— without being told to do so. The pharmaceutical formulation scientist has expertise in excipient compatibility, stability testing, drug delivery systems, and regulatory guidelines (cGMP), enabling them to optimize bioavailability and product shelf-life.
In addition, the prior art itself reflects an appropriate level (MPEP 2141.03(II)).
Determination of the scope and content of the prior art
(MPEP 2141.01)
Regarding claims 1, 2, 5, 8, 10-12, 16 and 17, Kim teaches spherical microparticles with an average particle diameter of 20 µm to 70 µm, which the Examiner interprets to read on the median particle size, and reads on a median particle size of between about 20 μm to about 60 μm, a median particle size of between about 25 μm and about 50 μm, a median particle size of about 20 μm to about 45 μm and a median particle size of between about 20 μm to about 55 μm, (See MPEP 2144.05(I): 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)), comprising a biodegradable polymer and a drug (Claim 1) where the drug is naltrexone (Claim 2) and the biodegradable polymer is a polyorthoester (Claim 6) and compositions of the microparticles (Claim 8), which would be pharmaceutical compositions comprising the spherical microparticle formulation.
Regarding claims 1, 2, 5, 8, 10-12, 16 and 17, Zale et al. teach microparticles of naltrexone and polyorthoester (Claim 1) wherein the mass median diameter of the microparticles is in the range of from about 20 µm to about 150 µm (Claim 8). Zale et al. teach a drug loading ranging from about 35% to about 39% for a process with 400 grams active agent and 600 grams of polymer (theoretical drug loading of 40%) (Example 7, column 16, lines 59-65).
Regarding claims 3, 4, 6, 7, 11 and 16, Bai et al. teach fabrication of polyorthoester microspheres where “All eight kinds of POE polymers used in this study are shown able to form microspheres under proposed fabrication conditions.” And: “POE containing 1,6-hexanediol diglycolide (HDdiGL) microspheres have the highest BSA release rate after a 20-day test through a combination of surface erosion and diffusion mechanisms. POE containing a high percentage of the trans-cyclohexanedimethanol (CDM) segment tends to yield microspheres with a lower release rate because of its hydrophobic nature.” (Abstract; Figure 2) Bai et al. show in Table 1 (Page 1632):
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Ascertainment of the difference between the prior art and the claims
(MPEP 2141.02) and Finding of prima facie obviousness
Rational and Motivation (MPEP 2142-2143)
The difference between the instant application and Kim is that Kim do not expressly teach wherein each polymer microsphere comprises a drug load of naltrexone or a salt thereof of greater than 40% by weight of the polymer microsphere or about 45% to about 60% by weight of the polymer microsphere; wherein the POE comprises a cyclohexanedimethanol:triethylene glycol (CHDM:TEG) co-polymer in a ratio of about 80: about 20; wherein the POE comprises a cyclohexanedimethanol:triethylene glycol:triethylene glycol glycolide (CHDM:TEG:TEG-GL) tri-block polymer in a ratio of about 88: about 10: about 2. This deficiency in Kim is cured by the teachings of Zale et al. and Bai.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the naltrexone polyorthoester spherical microparticles of Kim wherein each polymer microsphere comprises a drug load of naltrexone or a salt thereof of greater than 40% by weight of the polymer microsphere or about 45% to about 60% by weight of the polymer microsphere; wherein the POE comprises a cyclohexanedimethanol:triethylene glycol (CHDM:TEG) co-polymer in a ratio of about 80: about 20; wherein the POE comprises a cyclohexanedimethanol:triethylene glycol:triethylene glycol glycolide (CHDM:TEG:TEG-GL) tri-block polymer in a ratio of about 88: about 10: about 2, as suggested by Zale et al. and Bai, and produce the instant invention. One of ordinary skill in the art would have been motivated to do this because for the following sound articulated reasoning with rational underpinning based upon the evidence. As noted above, Bai teaches the claimed microsphere formulation of claim 1 except for the drug load of naltrexone or salt thereof of greater than 40% by weight of the polymer microsphere. However, Zale et al. teach an expectation of about 39% loading from a process with 400 grams active agent and 600 grams of polymer (theoretical drug loading of 40%). Not only does the term “about” provide for values greater than 39% such as 41% but also the loading would be result effective variable where a process with 500 grams of naltrexone and 500 grams of polymer would be expected to provide a 50% by weight loading of naltrexone or salt thereof with a reasonable expectation of success. Thus, a loading of greater than 40% by weight of the polymer microsphere or about 45% to about 60% by weight of the polymer microsphere is merely routine optimization by the ordinary artisan. Selection of the salt of naltrexone is within the skill of the ordinary artisan in the pharmaceutical arts.
As noted above, Kim and Zale et al. teach polyorthoesters for the biodegradable polymer but do not specify any particular polyorthoester. However, Bai teaches polyorthoester co-polymers comprising cyclohexanedimethanol:triethylene glycol in a 75:20 ratio (Table II, POE2, POE3), which reasonable reads on co-polymer in a ratio of about 80:about 20, and tri-block co-polymers comprising CDM/TEG/TEGmGL 94/5/1 (Table 2, POE8) as well as CDM/TEG/CDMmLT 5 89/10/1 (POE4). Consequently, it is merely routine optimization to obtain a tri-block copolymer comprising a cyclohexanedimethanol:triethylene glycol:triethylene glycol glycolide (CHDM:TEG:TEG-GL) tri-block polymer in a ratio of about 88: about 10: about 2. Especially when Bai teaches that the GL amount influences the release rate (Abstract; page 1631, left column 1st paragraph; page 1639, left column 2nd and 3rd paragraphs). Thus, it is merely routine optimization to tune the microparticle for the desired release rate with a reasonable expectation of success.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103.
Response to Arguments:
Applicant’s arguments filed 5/19/26 have been carefully considered but are not persuasive.
On page 2 of remarks, Applicant asserts that Kim only teaches PLGA microspheres for naltrexone and a polymer:drug ratio of 4:1 to 9:1. Respectfully, the Examiner does not agree with Applicant’s analysis of Kim. Kim is broader in scope because Kim claims a biodegradable polymer to drug weight ratio of 2:1 to 9:1 (Claim 5). While the Examiner does acknowledge that a 2:1 ratio represents a 66.67% polymer and 33.33% drug, such is not sufficient to remove Kim as prior art against the claimed subject matter. The reference of Kim remains valid because Kim teaches that while it is more difficult for the artisan to formulate the microparticles with uniformly distributed drug in the spherical biodegradable polymer as the amount of drug is increased beyond a 2:1 polymer:drug ratio [0060], hence more than 33.33% drug, it is not impossible. Difficulty is not the same as teaching away and obviousness is determined in light of all the facts. In fact, the secondary reference of Zale et al. suggests drug loading of about 39% (The term “about” provides for values greater than 39% such as 41%, which is also reasonably within the scope of the claimed “about 45%”. Especially when the specification teaches that the term “about’ includes ± 10% of the number. Thus, “about 45% includes a lower value of 45%-4.5% = 40.5%.) in microparticles of naltrexone and polyorthoesters, which provides a reasonable expectation of success in producing a microsphere formulation with a drug load of naltrexone of greater than 40% by weight of the polymer microsphere. There does not appear to be anything in the references which would lead an artisan in a direction divergent from the path that was taken by the applicant. Even if Applicant removed the term “about”, the claimed range and the prior art range are so close that the ordinary artisan would expect the same properties. See MPEP 2144.05(I): “Similarly, a prima facie case of obviousness exists where the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have the same properties. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985).”
On page 3 of remarks, Applicant argues that Zale only describes microparticles having about 35% to about 39% drug load of risperidone. However, that exemplary embodiment of Zale includes the scope of other active agents such as naltrexone. Zale states in Example 7:
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After that Zale provides an embodiment using risperidone. Consequently, the ordinary artisan readily extrapolates the teachings of Zale to include the other active agents taught by Zale, which include naltrexone. It is well-established that consideration of a reference is not limited to the preferred embodiments or working examples, but extends to the entire disclosure for what it fairly teaches, when viewed in light of the submitted knowledge in the art, to a person of ordinary skill in the art. (Merck & Co. v. Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed. Cir. 1989). Respectfully, Applicant’s arguments have been carefully considered but are not persuasive.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERNST V ARNOLD whose telephone number is (571)272-8509. The examiner can normally be reached M-F 7-3:30.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Brian Y Kwon can be reached at 571-272-0581. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ERNST V ARNOLD/Primary Examiner, Art Unit 1613
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