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 .
Claim Interpretation
Claim 1 recites the transitional phrase “comprising” which is inclusive or open-ended and does not exclude additional, unrecited elements or method steps (MPEP § 2111.03).
BRI of “a poly-L-lysine modified with 4-carboxy-3-fluorophenylboronic acid” includes poly-L-lysine and any polymer that comprises poly-L-lysine that is modified with 4-carboxy-3-fluorophenylboronic acid.
BRI of “loaded with insulin to form a polymer-insulin complex” includes insulin in complex with a poly-L-lysine modified with 4-carboxy-3-fluorophenylboronic acid alone and with additional, unrecited elements.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2-4 and 19-21 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 2-4 and 19-21, the parenthetical phrase "(weight basis)" renders the claim indefinite because it is unclear whether the limitation in parentheses are part of the claimed invention. See MPEP § 2173.05(d).
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-2, 4-7, 9, 10-11, 13, and 15-16 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lv et al. (Injectable dual glucose-responsive hydrogel-micelle composite for mimicking physiological basal and prandial insulin delivery. Sci China Chem, May 2019, Vol. 62, No. 5, 637-648; NPL 3, IDS 1/18/2025).
Lv et al. teach a material comprising a poly-L-lysine (PLL) modified with 4-carboxy-3-fluorophenylboronic acid (FPBA), namely p(Lys-co-LysFCPBA)-b-PEG-P(Lys-co- LysFCPBA) (Section 2.5). The PLL modified with FPBA is loaded with micelles that contain insulin to yield an insulin-loaded hydrogel-micelle composite (Section 2.8). Under hypergyclemic conditions, the insulin-loaded hydrogel-micelle composite releases insulin in a glucose-dependent manner. Under euglycemic conditions, insulin release is controlled (Scheme 1). The material taught by Lv et al. falls within the BRI of claim 1 outlined above. Therefore, Lv et al. satisfies all of the limitations of and anticipates claim 1.
Regarding claims 2 and 4, Lv et al. teach that the p(Lys-co-LysFCPBA)-b-PEG-P(Lys-co- LysFCPBA) is combined with an equal concentration of insulin-loaded micelles (Section 2.8).
Regarding claims 5-6, Lv et al. teach that the modification degree of FCPBA onto Lys is 46.6% (Section 2.5), which correspond to x is 1 (about 0.9, about 0.65) and y is 0.5 (within about 0.8 to about 0.1, about 0.6 to about 0.35).
With respect to claim 7, Lv et al. teach that the insulin-loaded hydrogel-micelle composite is maintained at pH 7.4 (Sections 2.6-2.8).
With respect to claim 9, Lv et al. teach the insulin-loaded hydrogel-micelle composite in an injection device (Section 2.11).
With respect to claims 10-11, 13, and 15-16, Lv et al. teach a method of injecting a volume of the insulin-loaded hydrogel-micelle composite to type 1 diabetic mice to alter glucose levels (Sections 2.11, 3.4). The blood glucose levels quickly reduced from 3.3 to 1.5 g/L in 1 hour and maintained a normal blood glucose level without hypoglycemia for up to nearly 24 hours (Section 3.4)
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.
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 1-11 and 13-24 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (Charge-switchable polymeric complex for glucose-responsive insulin delivery in mice and pigs. Sci. Adv.5,eaaw4357(2019), published 10 July 2019) in view of Tzannis (WO 2008/013955 A2) and Lv et al. (NPL 3, IDS 1/18/2025).
The factual inquiries for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) 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.
Determining the scope and contents of the prior art.
Wang et al. teach a glucose-responsive insulin delivery formulation comprising a polymer modified with 4-carboxy-3-fluorophenylboronic acid (FPBA) groups. In phosphate-buffered saline at pH 7.4 (PBS 7.4), the polymer is positively charged and forms a stable micro-sized suspension with a high insulin loading efficiency. Because glucose binding to FPBA decreases the positive charge density of the polymer, insulin binding to the polymer is glucose concentration dependent. Under hyperglycemic conditions, insulin is released from the polymer. Under normoglycemic conditions, this effect is reversed thereby reducing the insulin release rate (p. 1, col 2; Figure 1):
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Wang et al. teach that the glucose-responsive polymer can be used to deliver insulin to diabetic subjects with a robust glucose-dependent insulin release profile. In a type 1 diabetic mouse model, the complex showed prolonged blood glucose–regulating ability as compared to native insulin, with a negligible risk for hypoglycemia (p. 5, col 2).
Ascertaining the differences between the prior art and the claims at issue.
Wang et al. does not teach that the polymer in the glucose-responsive insulin is poly-L-lysine (PLL).
Resolving the level of ordinary skill in the pertinent art.
Poly-L-lysine is a polymer known in the art to be useful for complexing with insulin (see e.g. Tzannis, abstract). Poly-l-lysine is a polymer known in the art to be capable of being modified with 4-carboxy-3-fluorophenylboronic acid (see e.g. Lv et al., section 2.5).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the poly-L-lysine polymer taught by Tzannis for the polymer in polymer poly(EDAA) in the glucose-responsive insulin material taught by Wang et al. The rationale for obviousness is simple substitution of one known element for another to obtain predictable results (MPEP § 2143.01(B)). The relevant findings for this rationale are as follows.
(1) The prior art contained a device (method, product, etc.) which differed from the claimed device by the substitution of some components (step, element, etc.) with other components. In the instant case, the primary reference teaches poly(EDAA0.4-FPBA0.6)–complexed insulin which differs from the claimed material by the substitution of poly-L-lysine for poly(EDAA). Therefore, prior art contained a product which differed from the claimed device by the substitution of some component with another component.
(2) The substituted components and their functions were known in the art. Tzannis teaches poly-L-lysine, which is the substituted component. The function of poly-L-lysine is known in the art because Tzannis teaches that poly-L-lysine is a positively-charged polymer capable of complexing with insulin (abstract). In addition, Lv et al. teach that the free amino groups in poly-L-lysine can be modified with FPBA (section 2.5). Therefore, the substituted components and their functions were known in the art.
(3) One of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have been predictable. One of ordinary skill in the art would expect that the poly-L-lysine can perform the function of being modified with FPBA in the combination because POSITA would recognize that the free amino groups in poly-L-lysine are available for modification in the same manner that the free amino groups in poly(EDAA) are available in Wang et al. (see e.g. Lv et al., section 2.5 for an example of lysine monomers being modified with FPBA). As a result of being modified with FPBA, POSITA would expect poly(Lys0.4-FPBA0.6)–complexed insulin to exhibit the glucose-responsiveness reported by Wang et al. for poly(EDAA0.4-FPBA0.6)–complexed insulin. Therefore, one of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have been predictable.
(4) Whatever additional findings based on the Graham factual inquiries may be necessary, in view of the facts of the case under consideration, to explain a conclusion of obviousness. The results reported in the specification are expected in view of the prior art of Wang et al.
The rationale to support a conclusion that the claim would have been obvious is that the substitution of one known element for another yields predictable results to one of ordinary skill in the art. Therefore, claim 1 is obvious over the cited art.
Regarding claims 2-4, Wang et al. teach that poly(EDAA0.4-FPBA0.6) and insulin with different weight ratios of poly(EDAA0.4-FPBA0.6) to insulin were prepared. The ratios include 2:1, 1:2, and 1:1 (Figure S3). Regarding claim 2, the ratio of 1:1 is “about equal”. Regarding claim 3, the ration of 2:1 is “about twice”. Regarding claim 4, the ratios 2:1 and 1:1 fall within the claimed range.
Regarding claims 5-6, Wang et al. teach poly(EDAA0.4-FPBA0.6) (p. 2, col 1), wherein x is 0.4 and y is 0.6, which fall within the ranges.
Regarding claim 7, Wang et al. teach pH 7.4 (p. 2, col 1).
Regarding claim 8, Tzannis teaches a poly-L-lysine molecular weight of 9.8 and 29.9 kDa (Table 1). Tzannis also tests insulin loading as a function of PLL molecular weight, testing 4-15, 15-30, 30-70, 70-150 and >300 kDa (para. [0187]). Because insulin loading ability is dependent on PLL molecular weight (para. [0187]), it would have been obvious to optimize the molecular weight utilized in the generation of the glucose-responsive material of Wang et al. The claimed range 30-70 kDa falls within the prior art range 4-15, 15-30, 30-70, 70-150 and >300 kDa and is therefore prima facie obvious.
Regarding claim 9, Wang et al. teach the glucose-responsive material in an injection device (p. 3; Figure 4).
Regarding claims 10 and 13, Wang et al. teach a method of using the glucose-responsive material comprising delivering the material to a subject with type I diabetes (p. 3; Figure 4).
Regarding claim 11, Wang et al. teach administration by subcutaneous injection (Figure 4).
Regarding claim 14, it would have been obvious to use the glucose-responsive material for treating type II diabetes in subjects in need of insulin therapy.
Regarding claims 15, Wang et al. teach that subcutaneous injection of the glucose-responsive material resulted in a robust glucose-dependent insulin release profile. In a type 1 diabetic mouse model, the complex showed prolonged blood glucose–regulating ability as compared to native insulin, while negligible hypoglycemia was observed at the dose studied (Figure 5, col 1; Figures 4-5).
Regarding claims 16-17, the particular normoglycemia period achieved from administration would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Regarding claim 18-24, Wang et al. teach a method of making the complex comprising the steps of dissolving insulin and poly(EDAA0.4- FPBA0.6) in acidified H2O (50 [Symbol font/0x6D]l) and mixing, adding NaOH aqueous solution to adjust the pH to 7.4, and adding PBS (10 mM, pH 7.4) (p. 7, col 1).
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 1-11 and 13-24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 19/116,597 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the reference claims anticipate or render obvious the instant claims.
Reference claim 1 recites a glucose-responsive insulin complex, comprising phenylboronic acid-based polylysine and insulin. Reference claim 17 states that the phenylboronic acid may be
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, satisfying instant claim 1.
Regarding claims 2-4, reference claim 7 wherein a mass ratio of the insulin to the phenylboronic acid-based polylysine is 1:(0.5-10). The claimed ranges of about equal, about twice the amount and about one to about two times the amount overlap with or fall within the range in the reference claim and are therefore prima facie obvious.
Regarding claims 5-6, reference claim 2 requires a grafting rate of the phenylboronic acid-based polylysine of 25% to 75%. The claimed ranges of x and y values overlap with or fall within the range in the reference claim and are therefore prima facie obvious.
Regarding claim 7, reference claim 9 teaches pH 7.4.
Regarding claim 8, reference claim 15 requires a polylysine molecular weight of 30 to 70 kg/mol polylysine.
Regarding claims 10 and 13-14, reference claims 11-13 recite treating diabetes, which includes type I and type II.
Regarding claims 9, 11, 15-17, it would have been obvious to use an injection route to administer the claimed material. The effect of the material on blood glucose modulation would occur as a result of administering the same material to the same subjects in the same manner.
Regarding claims 18-24, reference claim 7 recites a method of making the material comprising dissolving the phenylboronic acid-based polylysine in weakly acidic water, mixing a solution of the phenylboronic acid-based polylysine with a solution of the insulin, and adjusting pH to a range of 6.5 to 8.0.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA MARCHETTI BRADLEY whose telephone number is (571)272-9044. The examiner can normally be reached Monday-Friday, 7 am - 3 pm.
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/CHRISTINA BRADLEY/Primary Examiner, Art Unit 1654