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 .
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 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.
DETAILED ACTION
Election/Restrictions - Groups
Restriction is required under 35 U.S.C. 121 and 372.
This application contains the following inventions or groups of inventions which are not so linked as to form a single general inventive concept under PCT Rule 13.1.
In accordance with 37 CFR 1.499, applicant is required, in reply to this action, to elect a single invention to which the claims must be restricted.
Group I, claims 1-8, drawn to an injectable pharmaceutical composition comprising an insulin analogue or derivative, collagen, and at least one additional excipient.
Group II, claims 9-11, drawn to a method for treating a metabolic disorder comprising administration of the composition of claim 1.
Group III, claims 12-13, drawn to a method of preparing the stable ultra long acting injectable solution of claim 1.
Group IV, claim 14, drawn to a method of modulating the release of the insulin analogue of claim 1.
As set for the in Rule 13.1 of the Patent Cooperation Treaty (PCT), “the international application shall relate to one invention only or to a group of inventions so linked as to from a single general inventive concept.” Moreover, as stated in PCT Rule 13.2, “where a group of inventions is claimed in one and the same international application, the requirement of unity of invention referred to in Rule 13.1 shall be fulfilled only when there is a technical relationship among those inventions involving one or more of the same or corresponding special technical features." Furthermore, Rule 13.2 defines “special technical features” as “those technical features that define a contribution which each of the claimed inventions, considered as a whole, makes over the prior art.”
The groups of inventions listed above do not relate to a single general inventive concept under PCT Rule 13.1 because, under PCT Rule 13.2, they lack the same or corresponding special technical features for the following reasons:
The special technical feature of Group I is a composition comprising a long acting insulin analog, collagen, and at least one excipient. This composition is not novel in view of the combination of Hori (“Enhanced Bioavailability of Subcutaneously Injected Insulin Coadministered with Collagen in Rats and Humans,” Pharmaceutical Research, Vol. 6, No. 9, 1989), in view of the Prescribing Information for Lantus (downloaded 4/3/2026 from https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021081s034lbl.pdf, dated June 2009), and Bolli (“Insulin analogues and their potential in the management of diabetes mellitus,” Diabetologia (1999) 42: 1151-1167). Hori teaches human subjects were administered a composition comprising porcine insulin with or without collagen subcutaneously (pg 814, left column). Hori teaches “When insulin was co-administered with collagen, the plasma insulin levels were higher than those of the control, and the hypoglycemic effect of insulin was also enhanced (pg 415, right column). Hori also teaches the degradation rate constant of insulin in the presence of collagen was less than half of the control (pg 815, left column, second and third lines).
Hori does not teach one or more excipients; the formation of a depot at physiological pH; or insulin glargine..
Bolli and the Prescribing Information for Lantus and teach the missing elements of Hori.
Bolli teaches insulin glargine is a long-acting analogue with neutral isoelectric point formed by addition of two positive charges (two arginine molecules) on the C-terminus of human insulin (pg 1160, right column). Bolli teaches the addition of the arginine molecules shifts the isoelectric point from a pH of 5.4 to 6.7±0.2 making the molecule more soluble at slightly acidic pH and less soluble at the physiological pH. Bolli teaches an additional change in the insulin glargine is the replacement of A21 asparagine by glycine is charge-neutral and as sociated with good stability of the resulting human insulin analogue, and the insulin glargine is injected as a clear solution of pH 4.0 which forms a microprecipitate at the physiologic, neutral pH (paragraph spanning pgs 1160 and 1161). Bolli teaches insulin glargine has a delayed and prolonged absorption from the injection site after subcutaneous injection (pg 1161, left column).
The Prescribing Information for Lantus teaches a 10 mL vial of glargine insulin (Lantus®) comprises the excipients meta-cresol (a preservative), zinc, glycerine, and the solubilizing agent polysorbate 20 and 100 IU of insulin glargine per mL (pg 12, Section 11 “Description”). These teachings read on claims 2-3. The Prescribing information also teaches that the microprecipitate formed after the exposure to physiological pH, from which small amounts of insulin glargine are slowly released, resulting in a relatively constant concentration/time profile over 24 hours with no pronounced peak. This profile allows once-daily dosing as a basal insulin. See pg 13, 12.2 Pharmacodynamics.
As such, Group I does not share a special technical feature with the instant claims of Groups II-IVI. Therefore, the claims are not so linked within the meaning of PCT Rule 13.2 so as to form a single inventive concept, and unity between Groups I-IV is broken.
Inventorship
Applicant is reminded that upon the cancellation of claims to a non-elected invention, the inventorship must be amended in compliance with 37 CFR 1.48(b) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. Any amendment of inventorship must be accompanied by a request under 37 CFR 1.48(b) and by the fee required under 37 CFR 1.17(i).
Rejoinder
The examiner has required restriction between product and process claims. Where applicant elects claims directed to the product, and the product claims are subsequently found allowable, withdrawn process claims that depend from or otherwise require all the limitations of the allowable product claim will be considered for rejoinder. All claims directed to a nonelected process invention must require all the limitations of an allowable product claim for that process invention to be rejoined.
In the event of rejoinder, the requirement for restriction between the product claims and the rejoined process claims will be withdrawn, and the rejoined process claims will be fully examined for patentability in accordance with 37 CFR 1.104. Thus, to be allowable, the rejoined claims must meet all criteria for patentability including the requirements of 35 U.S.C. 101, 102, 103 and 112. Until all claims to the elected product are found allowable, an otherwise proper restriction requirement between product claims and process claims may be maintained. Withdrawn process claims that are not commensurate in scope with an allowable product claim will not be rejoined. See MPEP § 821.04(b). Additionally, in order to retain the right to rejoinder in accordance with the above policy, applicant is advised that the process claims should be amended during prosecution to require the limitations of the product claims. Failure to do so may result in a loss of the right to rejoinder. Further, note that the prohibition against double patenting rejections of 35 U.S.C. 121 does not apply where the restriction requirement is withdrawn by the examiner before the patent issues. See MPEP § 804.01.
Telephonic Election
During a telephone conversation with attorney Hyunseok Park on March 9, 2026, a provisional election was made without traverse to prosecute the invention of Group I, claims 1-8. Affirmation of this election must be made by applicant in replying to this Office action. Claims 9-14 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to non-elected inventions.
Claim Status
Claims 1-14 are pending.
Claims 9-14 are withdrawn.
Claims 1-8 are examined on the merits in this prosecution.
Claim Objections
Claim 1 is objected to because of the following informalities: in the fifth line, the term “Wherein” should not be capitalized. Appropriate correction is required.
It is unclear what is the meaning of the word “one” at the end of the second line of claim 8. Appropriate correction or an explanation is required.
CLAIM REJECTIONS
Indefiniteness Rejection
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.
Claims 1-8 are rejected under 35 U.S.C. 112(b) 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.
Claims 1-8 recite the term “ultra long acting injectable pharmaceutical composition.” While several forms of insulin, including glargine insulin, are considered “long acting” forms, the instant specification provides no guidance regarding what the term “ultra long acting” signifies. As set forth in MPEP 2173.05(b), “If the specification does not provide some standard for measuring that degree, a determination must be made as to whether one of ordinary skill in the art could nevertheless ascertain the scope of the claim (e.g., a standard that is recognized in the art for measuring the meaning of the term of degree).” In the instant case, the specification provides no standard recognized in the art for measuring the term “ultra long acting.”
Claim 1 recites the term “the pharmaceutical composition exhibits increased bioavailability and longer duration of action compared to the marketed composition comprising the said ‘insulin analogue or derivative having an isoelectric point between 5 and 8.5’ at the same dose.” As set forth in MPEP 2173.05(b)(II),
A claim may be rendered indefinite when a limitation of the claim is defined by reference to an object and the relationship between the limitation and the object is not sufficiently defined. That is, where the elements of a claim have two or more plausible constructions such that the examiner cannot readily ascertain positional relationship of the elements, the claim may be rendered indefinite. See, e.g., Ex parte Miyazaki, 89 USPQ2d 1207 (Bd. Pat. App. & Inter. 2008) (precedential) and Ex parte Brummer, 12 USPQ2d 1653 (Bd. Pat. App. & Inter. 1989).
In the instant case, the “marketed composition” is not defined with regard to a specific composition, and currently marketed insulin compositions comprise a significant number of insulin analogs with the claimed isoelectric point, including several marketed compositions comprising glargine insulin, and the disclosure does not specify which insulin analog composition is the comparator.
Claim 7 recites the term: “the pharmaceutical composition is less immunogenic compared to the marketed composition comprising the said ‘insulin analogue or derivative having an isoelectric point between 5 and 8.5’ at the same dose.” As discussed above, the claim is considered indefinite since it is unclear what is meant by the term “the marketed composition comprising the said ‘insulin analogue or derivative having an isoelectric point between 5 and 8.5” since there are many marketed insulin analogs meeting the limitation of “an isoelectric point between 5 and 8.5” and the disclosure is not specific regarding what insulin analog composition is the comparator.
For the purposes of this examination, the Examiner, arguendo, considers the marketed composition Lantos® glargine insulin.
Obviousness Rejection
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 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.
1) Claims 1-3 and 5-8 are rejected under 35 U.S.C. 103 as being unpatentable over Hori (“Enhanced Bioavailability of Subcutaneously Injected Insulin Coadministered with Collagen in Rats and Humans,” Pharmaceutical Research, Vol. 6, No. 9, 1989), in view of the Prescribing Information for Lantus (downloaded 4/3/2026 from https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021081s034lbl.pdf, dated June 2009), and Bolli (“Insulin analogues and their potential in the management of diabetes mellitus,” Diabetologia (1999) 42: 1151-1167).
Hori teaches human subjects were administered a composition comprising porcine insulin (0.1 U/kg) with or without atelo collagen (0.5 μg/kg) subcutaneously (pg 814, left column). Hori teaches “When insulin was coadministered with collagen, the plasma insulin levels were higher than those of the control, and the hypoglycemic effect of insulin was also enhanced (pg 415, right column).
Hori also teaches the degradation rate constant of insulin in the presence of collagen was less than half of the control (pg 815, left column, second and third lines).
Hori does not teach one or more excipients; the formation of a depot at physiological pH; or insulin glargine..
Bolli and the Prescribing Information for Lantus and teach the missing elements of Hori.
Bolli teaches insulin glargine is a long-acting analogue with neutral isoelectric point formed by addition of two positive charges (two arginine molecules) on the C-terminus of human insulin (pg 1160, right column). Bolli teaches the addition of the arginine molecules shifts the isoelectric point from a pH of 5.4 to 6.7±0.2 making the molecule more soluble at slightly acidic pH and less soluble at the physiological pH. Bolli teaches an additional change in the insulin glargine is the replacement of A21 asparagine by glycine is charge-neutral and as sociated with good stability of the resulting human insulin analogue, and the insulin glargine is injected as a clear solution of pH 4.0 which forms a microprecipitate at the physiologic, neutral pH (paragraph spanning pgs 1160 and 1161). Bolli teaches insulin glargine has a delayed and prolonged absorption from the injection site after subcutaneous injection (pg 1161, left column).
The Prescribing Information for Lantus teaches a 10 mL vial of glargine insulin (Lantus®) comprises the excipients meta-cresol (a preservative), zinc, glycerine, and the solubilizing agent polysorbate 20 and 100 IU of insulin glargine per mL (pg 12, Section 11 “Description”). These teachings read on claims 2-3. The Prescribing information also teaches that the microprecipitate formed after the exposure to physiological pH, from which small amounts of insulin glargine are slowly released, resulting in a relatively constant concentration/time profile over 24 hours with no pronounced peak. This profile allows once-daily dosing as a basal insulin. See pg 13, 12.2 Pharmacodynamics.
For claim 5, the person of ordinary skill would have had a reasonable expectation of success in preparing an injectable with a mode of action of greater than 24 hours since The Prescribing information for Lantos teaches the release of insulin glargine occurs in a relatively constant rate over 24 hours and Hori teaches the degradation of insulin was reduced by half in the presence of collagen.
For claim 6, since the composition taught by Hori has an improved duration of action by two-fold in view of the addition of collagen, and the duration of action taught by The Prescribing Information for Lantus and Bolli is 24 hours, one of ordinary skill in the art, one of ordinary skill would be able to predict that the level of circulating insulin would increase and the frequency of injecting insulin would decrease, and the skilled artisan would have expected that the composition of the combination of the Hori, The Prescribing information for Lantos, and Bolli would have had the same duration of action as that which is instantly claimed. Something which is old (e.g. the composition taught by the combination of the Hori, The Prescribing information for Lantos, and Bolli) does not become patentable upon the discovery of a new property (e.g. the frequency of administration), and this feature need not have been recognized at the time of the invention. See MPEP 2112(I & II).
For the limitation of claim 7 of the claimed composition “is less immunogenic compared to the marketed composition,” since the composition taught by the combination of Hori, The Prescribing Information for Lantus, and Bolli appears to overlap with the claimed composition, the skilled artisan would have expected that the composition of the combination of Hori, The Prescribing Information for Lantus, and Bolli would have had the same immunogenicity as that which is instantly claimed. Something which is old (e.g. the composition of the combination of Hori, The Prescribing Information for Lantus, and Bolli) does not become patentable upon the discovery of a new property (e.g. the immunogenicity), and this feature need not have been recognized at the time of the invention. See MPEP 2112(I & II).
For claim 8, the skilled artisan would have expected success in adding a preservative such as meta-cresol and a solubility enhancer such as polysorbate 20 to the composition of Hori, as taught by The Prescribing Information for Lantus, and Bolli, since The Prescribing Information for Lantus and Bolli teach that addition of a preservative such as meta-cresol and a solubility enhancer such as polysorbate 20 are safe to employ in a composition for subcutaneous injection and useful in preserving the insulin composition and keeping the composition solubilized at pH 4.
2) Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Hori (cited above), in view of the Prescribing Information for Lantus (cited above), Bolli (cited above), and Friess (“Collagen - biomaterial for drug delivery,” European Journal of Pharmaceutics and Biopharmaceutics 45 (1998) 113-136).
The teachings of Hori, The Prescribing Information for Lantus, and Bolli, are discussed above.
The combination of Hori, The Prescribing Information for Lantus, and Bolli does not teach the composition comprising the collagen as human collagen.
Friess teaches the missing element of the combination of Hori, The Prescribing Information for Lantus, and Bolli.
Friess teaches collagen as a biomaterial useful for drug delivery (Title, Abstract). Friess teaches that animal derived collagen may cause an immune response upon injection, while human collage is free of immune response. Friess teaches an example wherein 5% of subjects injected with bovine collagen showed either an elevated antibody level or a reaction to a second injection (pg 117, 3.2. Antigenicity and immunogenicity).
The person of ordinary skill would have been motivated to substitute human collagen for animal collagen in the composition taught by the combination of Hori, The Prescribing Information for Lantus, and Bolli since Friess teaches that a 5% of subjects receiving an injection of animal collagen had a measurable antigenic reaction.
CONCLUSION
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MICHAEL P COHEN whose telephone number is (571)270-7402. The examiner can normally be reached on M-Th 8:30-5:30; F 9-4.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sahana S. Kaup, can be reached on (571) 272-6897. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MICHAEL P COHEN/Primary Examiner, Art Unit 1612
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