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 .
DETAILED ACTION
Claims 49 and 51-68 are pending in the Claim Set filed 10/29/2025
Applicants’ species election: an aminoglycoside antibiotic; Gentamycin (Antibiotic); Injection (Formulation is administered by); Bacteria (Infection caused by microbial).
Claims 58-67 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Herein, claims 49, 51-57 and 68 are for examination to the extent that they read on the elected species.
Withdrawn Rejections
The rejection of claims 54-57 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the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention is withdrawn in view of the amendments to the claims.
The rejections of claims 49 and 51-57 under 35 U.S.C. 102(a)(1) as being anticipated by Ickowicz et al (Poly(ester-anhydride) for controlled delivery of hydrophilic drugs. Journal of Bioactive and Compatible Polymers, p.127 August 2016 as evidenced by the specification is withdrawn in view of the amendments to the claims.
The rejection of claims 49, 50 and 68 under 35 U.S.C. 103 as being unpatentable over Ickowicz et al (Poly(ester-anhydride) for controlled delivery of hydrophilic drugs. Journal of Bioactive and Compatible Polymers, p.127 August 2016 [Ickowicz] in view of Krasko et al (Poly(ester anhydride)s Prepared by the Insertion of Ricinoleic Acid into Poly(sebacic acid), Journal of Polymer Science: Part A: Polymer Chemistry, p.1059, Feb. 2003 is withdrawn in view of the amendments in favor of the New Grounds of Rejection set forth below.
New Grounds of Rejection necessitated by 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 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.
Claims 49, 51-57 and 68 are rejected under 35 U.S.C. 103 as being unpatentable over Ickowicz et al (Poly(ester-anhydride) for controlled delivery of hydrophilic drugs. Journal of Bioactive and Compatible Polymers, p.127 August 2016, of record) [Ickowicz] in view of Domb et al (Stable polyanhydride synthesized from sebacic acid and ricinoleic acid, Journal of Controlled Release April 2016, p.156) [Domb] and Krasko et al (Poly(ester anhydride)s Prepared by the Insertion of Ricinoleic Acid into Poly(sebacic acid), Journal of Polymer Science: Part A: Polymer Chemistry, p.1059, Feb. 2003, of record) [Krasko].
Regarding claims 49 and 53,
Ickowicz teaches injectable pasty polyester-anhydride based on sebacic acid (SA) and ricinoleic acid (RA) at a 30:70 w/w ratio, that is poly(sebacic-co-ricinoleicester-anhydride) 3:7 (Abstract; Scheme 1; Table 1, p.132; Figure 7; Conclusion, p.137). Ickowicz teaches gentamicin sulfate (antibiotic: elected species) loaded polymer formulations of 10-20% w/w were prepared by mixing dry powder of the drug into pasty polymer: poly(sebacic-co-ricinoleic-ester-anhydride) 3:7) p(SA:RA) 3.7 (p.135; Figure 8). Ickowicz teaches gentamicin sulfate loaded) p(SA:RA) formulations are loaded in a syringe (p.131). Ickowicz teaches molecular weight of poly(sebacic-co-ricinoleic-ester-anhydride) 3:7 for Mn (Da) is 3900 Da and Mw (Da) is 7000. So, the Mw/Mn value is 1.8 (1.8 Mw/Mn as taught by Ickowicz lies within the Mw/Mn value between 1 and 2.5 (Claim 49; injectable formulation claim 53). (Table 1, p132).
Ickowicz does not teach that p(SA:RA)3.7 has an alternating structure -(SA-RA)n-.having a repeat unit of –(SA:RA)n where n is an integer between 10 and 100.
However, Domb and Krasko, as a whole, cure the deficiencies.
Domb teaches poly(anhydride) from ricinoleic (RA) and sebacic (SA) acid with alternating ester-anhydride structure that is stable at 25 °C for over 18 months. The polymer hydrolyses through anhydride cleavage lasting ~7 days to form oligoesters, which are stable for >30 days. The release of gentamycin from the synthesized alternate polymer matrix is sustained compared to the random copolymer (Abstract; See Fig.6, p162). Scheme on page 157 shows p(SA-RA) having an alternating structure, shown below:
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Particularly, Domb teaches 70 g RA and 30 g PSA (i.e., p(SA:RA)3.7 were mixed and melt at 175 °C under inert nitrogen atmosphere. The molten mixture was stirred for 24 h under inert atmosphere until no free RA remains in the reaction mixture. After 24 h, 5 equivalents of acetic anhydride were added and refluxed at 140 °C for 30 min. Excess acetic anhydride or acetic acid was evaporated. The residue was then subjected to melt condensation at 160 °C under vacuum (~10 m bar) for 6 h. (Section 2.5.4, p.158). Domb teaches the RA-SA copolymers were synthesized through melt polycondensation. The synthesis involved the esterification reaction of RA onto sebacic acid polyanhydride (PSA) to form carboxylic acid terminated oligomers, followed by anhydride polymerization to form P(RA-SA) (See Section 3.1, p.159; See entire document).
Moreover, Domb teaches that the alternating architecture provides improved stabilization hindering hydrolytic cleavage and anhydride interchange (Section 3.3, p.160). Further, Domb teaches that alternate RA-SA polymer's RA side chains prevent interchange by steric hindrance-imparting stability (p.161; See Scheme 2 on page 160). Moreover, Domb teaches random (RA-SA) copolymer are unstable (left col., top, p.161).
Krasko teaches that p(SA:RA)3.7 having a number average molecular weight (Mn) of 8000 & weight average molecular weight (Mw) 9000 (Mw/Mn = 1.125) (See Table 1, p.1062). The degree of polymerization (also called average number of repeat units (n)) is calculated herein by dividing Mn by molecular weight of the repeating unit (Mo), e.g., n = Mn/ Mo: in this case: molecular weight of repeat unit SA:RA = about 500 g/mol, So that, 8000 (Mn) / 500) = 16.
Therefore, Krasko teaches that p(SA:RA)3.7 having about 16 repeat units = –(SA:RS)16, of which n= 16 lies within the claimed values.
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, 91 9 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). MPEP 2144.05
Krasko teaches that poly(sebacic-co-ricinoleic-ester-anhydride) 3:7 have potential use as drug carriers (Abstract). Krasko teaches p(SA:RA)3.7 with greater than 60% RA, e.g., p(SA:RA)3.7 (Mw/Mn = 1.125) provided slow release of a drug over 400 hours and provided enhanced thermal stability (Figure 7; Table 2). Moreover, Krasko teaches polymer Mw enhances storage stability Mw for p(SA:RA)3.7 (Table 2; See entire document).
It would have been obvious to modify the teachings of Ickowicz to provide an antimicrobial formulation comprising gentamicin and a carrier in a form of a polyanhydride having an alternating structure -(SA-RA)n-, where n is an integer between 10 and 100, particularly, n = 16, and wherein the carrier having a Mw/Mn value between 1 and 2.5, particularly, Mw/Mn value is 1.8, in view of the teachings of Domb and Krasko, as a whole.
One skilled in the art would have been motivated to do so because polyanhydrides alternating architecture provide improved stabilization hindering hydrolytic cleavage and anhydride interchange whereas random (RA-SA) copolymer is unstable as taught by Domb. Further, polyanhydrides p(SA-RA) have improves the storage stability and drug release properties as taught by Krasko.
Claims 51 and 52 are product-by-process claims. 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 art product was made by a different process. "In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985). Even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. See MPEP § 2113. Accordingly, there is no physical evidence to support or a reason to believe that a patentably distinct structure is imparted by the process steps of claims 51 and 52. See MPEP 2113.
Claims 54-56, gentamicin sulfate is necessarily effective against bacterium. "A chemical composition and its properties are inseparable.” Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. In re Spada 15 USPQ2d 1655, 1658 (Fed. Cir. 1990), e.g., gentamicin is necessarily effective against bacterium, e.g., Staphylococcal aureus (a gram-positive cocci bacteria) as evidenced by Example 7 and pg. 9 of the specification.
Claim 57 is intended use of the antibiotic. A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. Since the prior art teaches particles that are structurally the same as those claimed, they must be at least capable of performing the intended use, as a composition and its properties are inseparable, supra.
Regarding claim 68,
Claim 68 recites a kit. There is no positive recitation of the kit ingredients/elements that distinguishes the claim over the cited prior art. Regarding the set of instructions present with the kit, for printed matter that is not functionally related to the product, the content of the printed matter will not distinguish the claimed product from the prior art. In re Ngai, 367 F.3d 1336, 1339, 70 USPQ2d 1862, 1864 (Fed. Cir. 2004)
Therefore, the teachings of Ickowicz, Domb and Krasko.as a whole, read on the claimed kit. Further, it is a well-known convention in the art to place for the advantages of convenience and economy and available to the ordinarily skilled artisan the claimed elements in a kit.
Response to Arguments
Applicants argue that there is nothing in Krasko that teaches a preparation of a polyanhydride having a repeat unit of -(SA:RS)n, wherein n is an integer between 10 and 100.
Applicant’s arguments have been fully considered but they are not persuasive, because one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of the teachings of Ickowicz , Domb and Krasko, as a whole. 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). Moreover, Ickowicz , Domb and Krasko are specifically directed to polyanhydrides comprising sebacic acid and ricinoleic acid that provide enhanced stability and release properties of an antibiotic, e,g, gentamicin, further comprising improved shelf life, wherein, as a whole, clearly exemplify that polyanhydrides -SA-RA- having alternating architecture are far superior over random polyanhydrides. As discussed above, it would have been obvious to those skilled in the art to provide –(SA-RA)16 in view of the teachings of Krasko having a reasonable expectation of success.
Applicants argue the polyanhydride of the invention having the formula -(SA-RA)n is not suggested by either Ickowicz or Krasko. A person of skill in the art would not know how to modify either publication to achieve a polyanhydride of the claimed structure. There is nothing in either publication to suggest a process as claimed
Applicant’s arguments have been fully considered but they are not persuasive, because one skilled in the art would have recognized that polyanhydrides –(SA-RA)- having an alternating structure (as claimed) are superior over random such polymer and would have looked to Domb for guidance in a process of preparing polyanhydrides –(SA-RA)- having an alternating architecture while having a reasonable expectation of success.
Applicants argue gentamicin loaded polymer formulations prepared according to the present invention, wherein the polymer had a narrow molecular weight and polydispersity, showed injectability with smooth release of the polymer or formulation from the syringes and needle with same force applied on the plunger. However, syringes loaded with the polymers and formulations of the prior art were inconsistent, with only two syringes able to release the polymer or the formulation using a regular force on plunger while three failed injectability and required extra force for allowing the formulation to pass through the needles. One syringe of the polymer and one of the formulations did not allow any release at room temperature. Also, formulations prepared with the polymers of this invention showed almost linear release profiles for the entire 28 days with a narrow standard deviation of between 1 and 5% of each data point. As compared, the release of gentamicin from the polymer formulations of the prior art was constant for the 28 days but the standard deviation was between 5 and 20% of the amount released at each time point. These comparative results clearly support our position that the polyanhydride of the invention is superior to that of Ickowicz or Krasko, alone or combined.
Applicant’s arguments have been fully considered but they are not persuasive, because Domb cures the deficiencies of Ickowicz or Krasko,
Particularly, Domb strongly emphases the superiority of polyanhydrides having specifically alternating structures wherein the release profile of gentamicin is superior to that of random polyanhydrides thereof, as exemplified in Fig. 6, shown below:
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Notably, the release profile shown in Fig. 6 for the alternating polyanhydride provides a substantially linear release profiles for gentamicin.
Domb teaches alternating poly(RA-SA)70:30 synthesized in a one pot process possess superior properties over previously reported polyanhydrides with regard to shelf-life stability, hydrolytic stability and stability towards anhydride interchange. The resulting polyanhydride is stable at room temperature for ~18 months. The hydrolysis pattern is slower compared to SA polyanhydride. This pasty RA-SA alternating polymer with high storage stability has a potential use as injectable carrier for the delivery of bioactive agents for periods of months.
Conclusions
No claim is 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.
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/T.W./Examiner, Art Unit 1619
/SARAH ALAWADI/ Primary Examiner, Art Unit 1619