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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 10/28/2025 has been entered.
Election/Restrictions
Applicant’s election of:
(i) insulin as active compound (known in the art to be a polypeptide); and
(ii) administration in multiple doses (claim 153),
claims 143-156 reading thereon, in the reply filed on 6/3/2024 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 149, 152, 154-155 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 6/3/2024.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 120 as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 62/588,008, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. Examiner’s review of the ‘088 application failed to identify any disclosure of CAGE with a generic active compound, being administered subcutaneously (insulin examples that are subcutaneously administered, disclosed in ‘008 are not construed to provide support for the currently broader claims) administration. The Examiner also did not identify the alternatives of claim 146. Accordingly, there is insufficient written description type support in the priority application corresponding to the current claims. Written description type support was identified in 62/681,861. Accordingly, the effective filing date of the instant application is the filing date of the ‘861 application, 6/7/2018.
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.
Claim(s) 143-148, 150-151, 153, 156 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zakrewsky et al. (US 2016/0263225 A1; 2016; cited in a prior Office action), in view of American Diabetes Association; “Insulin Administration”; 2004; Diabetes Care; 27(Suppl. 1): S106-S109; cited in a prior Office actio.
Zakrewsky teaches compositions and methods, that can be tuned and modified such that they can be used to treat a variety of different diseases and disorders, where compositions contain neat ionic liquids, optionally in combination with a drug to be delivered (abstract).
In Figure 2B, LANL-21 was used with Cefadroxil, providing an enhanced ratio in dermis relative to SC. Choline geranate 1:2 was used as one alternative in Fig. 6.
Choline geranate is also taught to be a deep eutectic solvent (DES) [0035].
Drugs to be delivered may be any chemical or biological molecules providing a therapeutic effect in vivo and may contain any suitable drug. The drug is selected based on the disease to be treated (p. 4, [0054], lines 1-6). Among those drugs contemplated are hypoglycemic agents, which include Applicant elected insulin (p. 5, right, lines [0054], p. 4, right, lines 5-7) (the Examiner notes that no claim is limited to insulin. And many other drugs are taught by Zakrewsky, [0053]-[0054]).
Choline Geranate (1:2, molar ratio) is an exemplary ionic liquid prepared [0094]. This ionic liquid combination is labeled LANL-21 (Table 2). The combination is lipophilic (Table 3 indicates log Po/w of 0.28; i.e., a ratio in octanol/water about 2:1, and 66% in octanol) [0160]. Concentration of 2.26 M is reported Table 5, indicating concentrations up to this level can be prepared.
Choline Geranate is clearly a preferable embodiment of ionic liquid and DES. The combination with Applicant elected insulin, reading on claims 143, 146, admixture of claim 148, is obvious from the teachings of Zakrewsky, including ratios of claims 145, 150-152, and a concentration of claim 144.
Compositions may be in the form of various dosage forms [0056]-[0057], which render obvious various pharmaceutically acceptable carriers known to prepare the forms listed (instant claim 147).
Regarding the required subcutaneously administering, Zakrewsky does mention subcutaneous [0003], even though this is less preferred (downside is use of needles), compared to topical/transdermal delivery Zakrewsky prefers [0011].
While Zakrewsky prefers topical application to skin/transdermal (e.g., [0060]), Zakrewsky also teaches tuning and modifying the methods such that they can be used to treat a variety of different diseases (abstract). When selecting insulin taught by Zakrewsky, the skilled artisan would have found obvious subcutaneous administration, standard administration route by diabetic patients as an appropriate tuning/modifying the Zakrewsky methods for treating type 2 diabetes.
American Diabetes Association teaches a position statement regarding insulin administration (title). An insulin regimen is often required in the treatment of gestational diabetes and diabetes associated with certain conditions or syndromes; in all instances of insulin use, the insulin dosage must be individualized and balanced with medical nutrition therapy and exercise (S106, 2nd paragraph).
Conventional insulin administration involves subcutaneous injection with syringes marked in insulin units (S107, middle, SYRINGES section, 1st paragraph); see also discussion of pen-like devices and insulin-containing cartridges that deliver insulin subcutaneously through a needle (S108, left-middle columns, bridging paragraph). American Diabetes Association establishes that a standard route of delivery of insulin is subcutaneously, rendering obvious this delivery route, when administering the Zakrewsky CAGE insulin formulations to a diabetic patient (a subject in need of the claimed delivery) (S109, last paragraph).
Regarding the elected multiple doses (claim 153), the delivery of insulin to obtain the best metabolic control involves understanding duration of action of insulin, relationship of blood glucose levels to exercise, food intake, intercurrent illness, certain medications, and stress, and learning to adjust insulin dosage to achieve individualized target goals (S109, last paragraph). In other words, for a diabetic patient using subcutaneous injections of insulin, the dosing is ongoing, taking account of the body’s need for insulin after meals, for instance. Thus, Applicant elected multiple doses are obvious, based on the glycemic control management needs of the patient.
Applicant argues:
The Office has allegedly not established the motivation required for a prima facie case of obviousness.
Applicant notes that "obviousness concerns whether a skilled artisan not only could have made but would have been motivated to make the combinations or modifications of prior art to arrive at the claimed invention." Belden Inc. v. Berk-TekLLC, 805 F.3d 1064, 1073 (Fed. Cir. 2015) (emphasis in original). An obvious rejection must include "some articulated reasoning with some rational underpinning to support the legal conclusion of obviousness." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007). Thus, it is the Office's burden to provide an articulated reasoning for why one of skill in the art would have made the proposed modification or substitution.
In addition, the MPEP is clear that "If a proposed modification would render the prior art invention being modified unsatisfactory for its intended purpose, there may be no suggestion or motivation to make the proposed modification." MPEP 2143.01(V).
The Office is improperly ignoring the teachings of Zakrewsky their intended purpose
Zakrewsky is clear that its disclosure and intended purpose relates to "topical and transdermal drug delivery." See Zakrewsky at title, abstract, [0002], and [0003]. Zakrewsky explicitly contrasts its topical and transdermal drug delivery with things such as "oral, subcutaneous, and intravenous." Id. at [0003]. Zakrewsky is further clear that its topical/transdermal compositions and methods have numerous advantages over oral, subcutaneous, and intravenous delivery. Id.
The Office does not explain why, on the basis of the cited art, one of skill in the art would be motivated to dispense with the advantages Zakrewsky claims and make a substitution that undoes the precise thing which Zakrewsky indicate has provided their advantages. Additionally, keeping in mind that Zakrewsky has invented topical/transdermal methods/formulations and not insulin itself, the Office is fundamentally altering the methods of Zakrewsky in a manner that would render them unsatisfactory for Zakrewsky's stated intended purpose of topical/transdermal administration, thereby running afoul of MPEP 2143.01(V).
The Office is improperly equating topical transdermal administration and subcutaneous
administration
The Office contends that undoing the basis of Zakrewsky's advantages is acceptably within the bounds of Zakrewsky's "tuning and modifying" because subcutaneous injection is "the standard delivery for insulin" and "this route has been shown to be useful in the type 2 diabetes treatment." FOA at 11. Thus, the Office is taking the position that because subcutaneous administration of insulin is used in the art, it is obvious for every insulin formulation to be administered subcutaneously. Applicant submits that this is improper and ignores the state of the art which was aware that different routes of administration are not interchangeable and do not operate by the same mechanisms.
For example, it is well known in the art that topical and subcutaneous administration of drugs results in the drugs proceeding to circulation via different routes and under different mechanisms or pressures. Topical/transdermal administration and subcutaneous administration are therefore not equivalent alternatives. For example, subcutaneous injections themselves are known to include protease activity in subcutaneous tissue and can induce antibody responses. See Mrsny ("Metabolic Processes at Injection Sites Affecting Pharmacokinetics, Pharmacodynamics, and Metabolism of Protein and Peptide Therapeutics" in Proteins and Peptides: Pharmacokinetic, Pharmacodynamic, and Metabolic Outcomes Elsevier. pg. 80-105 (2009); submitted herewith) at 85-87. Subcutaneous administration of small proteins proceeds primarily through the vasculature. Id. at 96. Additionally, it is well known in the art that administration to the dermis preferentially proceeds through the lymphatic system as compared to subcutaneous administration. Id. at 98.
A formulation appropriate for dermal administration (e.g., the topical/transdermal administration of Zakrewsky) is appropriate for conveying a drug through the lymph system, an environment characterized by white blood cells. In contrast, a formulation appropriate for subcutaneous administration must contend with potential protease and antibody responses and shepherd the drug into the vasculature. There is no evidentiary basis that a formulation for dermal administration is generally expected to be appropriate for subcutaneous administration. Therefore, using a topical formulation in subcutaneous administration is not obvious and is well beyond the bounds of Zakrewsky's "tuning and modifying."
The ADA reference cannot supply the foregoing defects
"It is impermissible within the framework of section 103 to pick and choose from any one reference only so much of it as will support a given position, to the exclusion of other parts necessary to the full appreciation of what such reference fairly suggests to one of ordinary skill in the art." In re Wesslau, 353 F.2d 238,241 (CCPA 1965). The Office cannot "stitch together an obviousness finding from discrete portions of prior art references without considering the references as a whole." In re Enhanced Security Research, LLC, 739 F.3d 1347, 1355 (Fed. Cir. 2014).
In the Advisory Action, the Office repeatedly asserts that the ADA reference establishes the "subcutaneous route" is "the standard route" for insulin administration. But this is ignoring the entirety of the ADA reference.
The inquiry is not whether the ADA reference teaches that subcutaneous administration of insulin is known in the art, but whether the ADA reference provides a motivation to alter Zakrewsky's methods from transdermal/topical administration to subcutaneous administration. There is nothing in the ADA reference that does so, and nothing that would overcome the teachings of Zakrewsky and state of the art described above.
Zakrewsky is explicit that they are describing topical/transdermal methods that solve problems they believe exist with subcutaneous administration. The ADA reference offers nothing to rebut this. It merely confirms the existence of the subcutaneous administration which Zakrewsky asserts they have improved upon by providing topical/transdermal methods. Thus, nothing in the art can provide a suggestion or motivation to modify Zakrewsky's methods to arrive at the instant methods.
In view of the foregoing, Applicants submit that the current claims are not obvious in light of any of the prior art provided. Reconsideration and withdrawal of the rejection under 35 U.S.C. @103, is respectfully requested.
In view of the above, Applicant submits that all issues raised in the Office Action are addressed herein. Entry of the proposed amendments and reconsideration of the claims is respectfully requested.
Applicant does not acquiesce in the Examiner's characterizations of the art including the alleged motivation to combine references. For brevity and to advance prosecution, however, applicants may have not addressed all characterizations of the art and reserve the right to do so in further prosecution of this or a subsequent application. The absence of an explicit response by the applicants to any of the Examiner's positions does not constitute a concession of the Examiner's positions. The fact that applicants' comments have focused on particular arguments does not constitute a concession that there are no other arguments for patentability of the claims. All of the dependent claims are patentable for at least the reasons given with respect to the claims on which they depend.
Applicant argues about Zakrewski teaching, with the emphasis of formulations for topical and transdermal delivery; but not for subcutaneous. The Examiner does not dispute this emphasis with Zakrewski. Zakrewski teaches Choline Geranate (as an exemplary ionic liquid, used with various drugs), and the specific instant elected drug, insulin, contemplated as hypoglycemic agent (although insulin as a specific drug is not required by instant claims). Thus, the combination of CAGE and insulin is clearly among the combinations taught.
However, the ADA article clearly establishes for insulin treatment of, for instance, diabetes, subcutaneous administration is a standard route of administration for treating diabetic patients. Zakrewsky also teaches tuning and modifying the methods such that they can be used to treat a variety of different diseases (abstract). When selecting insulin taught by Zakrewsky, the skilled artisan would have found obvious subcutaneous administration, clearly recognized in the prior art as the standard administration route by diabetic patients, as an appropriate tuning/modifying the Zakrewsky methods for treating type 2 diabetes.
While it is true that Zakrewsky does not prefer subcutaneous administration because of the needles used in the route, the art-recognized standard route for treating diabetic patients with insulin would have outweighed the negative needles consideration. It is sufficient to render obvious the standard subcutaneous administration in place of the Zakrewsky administration route. Applicant alleges that subcutaneous administration is considered a type of systemic administration, and somehow this would render side effects to be a teaching away from the claimed method. Any preference against subcutaneous by reading into Zakrewsky as somehow teaching away from subcutaneous based on alleged, but not shown, side effects would have been clearly mitigated by the recognition of the ADA article that insulin administration by subcutaneous route as the standard route routinely used in the prior art. Whatever known side effects would already be standard in the art for this insulin treatment, and would not be a teaching away from subcutaneous administration. Regarding teaching away, MPEP 2145 (X)(D)(1) indicates A prior art reference that "teaches away" from the claimed invention is a significant factor to be considered in determining obviousness. However, "the nature of the teaching is highly relevant and must be weighed in substance. 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, 553, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994). When the teaching away from subcutaneous of Zakrewsky is considered, the downside is the use of needles. However, when weighing the ADA articles clearly establishing subcutaneous dosing of insulin is a standard delivery route, the skilled artisan would have recognized that the teaching of subcutaneous dosing outweighs the preference against needles used for subcutaneous dosing.
Regarding the argument that combination of insulin and a second drug (when CAGE is a drug) is not preferred, Zakrewsky does teach this as one alternative, but also teaches CAGE which is not a drug. This embodiment has no relevance to the argument.
Thus, motivation to modify the teachings of the references is stated in the rejection basis, and in rebuttal arguments. Thus, motivation has been articulated.
Teachings of Zakrewski have not been ignored. The formulation of CAGE with insulin are clearly relied on. The rejection relies on alternate administration route of subcutaneous taught by the ADA reference as being standard.
Regarding the allegation that the rejection somehow equates topical and subcutaneous, this is not accurate. Both are art recognized for administration of insulin products. Thus, it would have been obvious to substitute subcutaneous from topical.
Applicant’s arguments seem to imply that a specific suggestion for this modification is required by ADA. The skilled artisan is not an automaton, but can fit teachings of multiple patents together like pieces of a puzzle, and take into account the interferences and creative steps that a person of ordinary skill in the art would employ.
"A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. at 420, 82 USPQ2d 1397. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418, 82 USPQ2d at 1396. MPEP 2141.03(I).
Examiner notes that in support of this rationale, (topical and subcutaneous are both taught in the art for insulin administration, and thus, it would have been obvious to substitute subcutaneous for topical).
As a rebuttal reference, Banerjee et al. (“Transdermal Protein Delivery Using Choline and Geranate (CAGE) Deep Eutectic Solvent”; 2017 March 24; Adv. Healthcare Mater.; 6: 1601411; pp. 1-11; doi.org/10.1002/adhm.201601411, which has inventors in common with the instant application, clearly documents CAGE/insulin and comparative formulation of insulin in buffer, are studied by using both topical application and subcutaneous insulation (see Figure 7), and observing the reduction in blood glucose levels. This documents that subcutaneous is an alternate administration route from topical application; the two are comparable for insulin administration, as having similar peak efficacy, but using different dosing (pp. 8-9, bridging paragraph). The evidence is consistent with the Examiner’s position that substitution of subcutaneous administration is an obvious alternative of topical administration for CAGE formulation of insulin.
Conclusion
No claims are allowed.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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 TIMOTHY P THOMAS whose telephone number is (571)272-8994. The examiner can normally be reached M-Th 6:30-5:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ali Soroush can be reached at (571)272-9925. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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TIMOTHY P. THOMAS
Primary Examiner
Art Unit 1614
/TIMOTHY P THOMAS/Primary Examiner, Art Unit 1614