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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 8/13/2025 has been entered.
Claim Status
Claims 1-3, 5-7, 10-11, 15-22, 24-26, 34-36, 38-42, 44-45, 47, 50-51, 69-85, and 88-95 are pending.
Claims 4, 8-9, 12-14, 23, 27-33, 37, 43, 46, 48-49, 52-68, and 86-87 are cancelled.
Claims 6, 47, 72, and 74-79 are withdrawn as being directed to a non-elected species, the election having been made on 4/15/2020.
Claims 1-3, 5, 7, 10-11, 15-22, 24-26, 34-36, 38-42, 44-45, 50-51, 69-71, 73, 80-85, and 88-95 have been examined.
Priority
This application is a 371 of PCT/GB2017/052941 filed on 09/29/2017, which claims foreign priority as follows:
UNITED KINGDOM 1616509.4 filed on 09/29/2016
UNITED KINGDOM 1617866.7 filed on 10/21/2016
UNITED KINGDOM 1707190.3 filed on 05/05/2017
New Ground of Objection and Rejection
Claim Objections
Claims 15, 51, and 71 are objected to because of the following informalities:
Claim 15 contains the acronyms “DETA” and “TETA”. An acronym in the first instance of claims should be expanded upon/spelled out as “diethylenetriamine” and “triethylenetetramine” with the acronyms indicated in parentheses as (DETA) and (TETA). The abbreviations can be used thereafter.
Claim 51 is object because the preamble “A formulation” should be revised to “The formulation”.
Claim 71 is object to because the acronyms “GLP-1” should be revised to “glucagon-like peptide-1 (GLP-1)” with the same reason of objection to claim 15 above.
Appropriate correction is required.
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.
Claim 10 is 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 10 recites the broad recitation of insulin concentration > 500 U/ml, and the claim also recites insulin concentration > 1000 U/ml which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 10 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 10 encompasses insulin concentration > 1000 U/ml, but fail to further limit the insulin concentration ranged from 500-1000 U/ml in claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Modified Rejection
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.
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.
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.
1. Claims 1-3, 5, 7, 10-11, 15-22, 34-36, 38-42, 44-45, 50-51, 69-71, 73, 80-85, and 88-95 are rejected under 35 U.S.C. 103 as being unpatentable over Akers et al. (WO 2016/100042 A1, previously cited in IDS dated 10/31/2019) in view of Bley et al. (US 2015/0190475, previously cited 8/25/2020) and evidenced by Humulin R (Lilly USA, LLC 2011).
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Claim 1 is drawn to an aqueous insulin formulation as follows.
With respect to the limitation (i), Akers et al. teach a composition of human insulin or insulin analog (Abstract). Akers et al. teach the human insulin analogs comprising insulin aspart (p9, line 27-30; claim 1). Akers et al. teach the insulin concentration is a result effective variable and optimized from about 100 to about 500 IU/ml (p13, line 8-9 and claim 3; including a concentration slightly above 500 IU/ml, e.g., 501 IU/ml), reading on the limitation (i). Consistently, Bley et al. teach the concentration of insulin analog can be optimized from 10 U/ml to 1000 U/ml [0014]. Humulin R is further cited to show the common knowledge of using the high concentration of insulin (e.g., RU-500; 500 U/mL) to treat insulin-resistant patients with diabetes requiring daily doses of more than 200 units via subcutaneous administration (p2, Indications and usage).
With respect to the limitation (ii), Akers et al. teach the composition comprising about 0.2 mM to about 2 mM zinc shown as follows (p23, line 16; claim 1). Akers et al. teach 1 unit
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of insulin aspart is equal to 0.035 mg (p12, line 22-23), reading on the limitation (ii) for a weight ratio of 2 mM Zn to 500 IU insulin as 0.74%.
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With respect to the limitation (iii), Akers et al. teach the insulin composition comprising about 10 to about 35mM of negatively charged citrate acid able to bind to zinc (p14, line 9, Cas No.: 77-92-9; p14, line 18). Although Akers et al. do not explicitly disclose logK of citrate, the specification disclosed a preferred zinc binding species of citrate with logK = 4.95 at 25 °C, (p8, last para), reading on the limitation (iii) as well as less than 0.1 mM zinc binding species having a logK with respect to zinc ion binding of more than 12.3 at 25°C in the wherein clause. MPEP 2112.01 (II) states "Products of identical chemical composition cannot have mutually exclusive properties"; thus, Akers’s citric acid inherent has logK = 4.95 at 25°C.
With respect to the limitation (iv), Akers et al. teach the insulin formulation beneficially comprising a stabilizing agent of surfactant in combination with magnesium (p19, 16-20). Akers et al. teach a surfactant, in a concentration from about 0.001 to about 0.2 % w/v (p4, line 10-11), equivalent to 10 μg/ml to about 200 μg/ml (w/v). Akers et al. show the surfactant is a non-ionic
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surfactant as a trehalose derivative of trehalose laurate ester, an alkyl glycoside, (p19, line 29) shown as follows, reading on an alkyl glycoside at 10-200 μg/ml.
Akers et al. teach if the total chloride content of the composition is too high, the insulin in the composition may crystallize (reading on aggregation) at low temperatures (p17, line 14-16); thus, one of ordinary skill in the art would minimize the use of chloride in a formulation to avoid aggregation of insulin. Bley et al. teach zinc acetate is a common compound to substitute zinc chloride for insulin formulation known in the art [0017]. Akers et al. suggest the insulin formulation may further comprise about 1 to about 50 mM NaCl (p19, line 7-15). In an insulin formulation comprising 0.2 mM ZnCl2 (p23, line 16; claim 1; can be replaced by zinc acetate as taught by Bley et al. [0017]), 1 mM MgCl2 (p23, line 28) and 1 mM NaCl (p19, line 10-11) as the major chloride resources, the low end of chloride concentration is estimated to be 3.4 mM calculated as (0.2 x 2 + 1 x 2 + 1), reading on less than 8 mM chloride. When 0.2 mM ZnCl2 is replaced by Zn-(acetate)2, the chloride concentration is even lower to 3 mM, far less than 8 mM chloride as claimed. See MPEP 2144.05. 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, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). In the present case, all the salts, excipients, and even the units of insulin taught by Akers et al. overlap with the claimed ranges. Akers et al. further teach, preferably, the route of insulin administration is by self-administered subcutaneous injection (p22, line 11), reading on not for administration by intranasal delivery in the wherein clause and satisfying the instant claims 1 and 21-22.
One of ordinary skill in the art before the effective filing date of this invention would have found it obvious to combine Akers’s insulin formulation with Bley et al. because (a) Akers et al. teach insulin formulation comprising zinc compound (p23, line 16; claim 1) and chloride may cause crystallization of insulin (reading on aggregation) at low temperatures (p17, line 14-16), and (b) Bley et al. teach the concentration of insulin analog can be optimized from 10 U/ml to 1000 U/ml [0014] and further suggest that zinc acetate can substitute zinc chloride [0017] able to reduce chloride concentration in an insulin formulation. The combination would have reasonable expectation of success because both references teach insulin formulation at high concentration of 500 U/ml or above. Humulin R is further cited to show the common knowledge of using the high concentration of insulin (e.g., RU-500; 500 U/mL) to treat insulin-resistant patients with diabetes requiring daily doses of more than 200 units via subcutaneous administration (p2, Indications and usage).
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With respect to claims 2-3, Akers’s insulin formulation comprising 0.2 mM Zn, 3 mM Mg, and 1 mM NaCl. The ionic strength of the composition is about 8 mM calculated above.
With respect to claims 5 and 7, Akers et al. teach the insulin can be the elected species of insulin aspart (p13, line 5-10).
With respect to claims 10 and 11, Akers et al. teach the concentration of insulin and its analogs can be optimized from about 100 to about 500 IU/ml, including a concentration slightly above 500 IU/ml (p13, line 9-10), reading on a concentration of > 500 U/ml. Bley et al. teach the concentration of insulin analog can be optimized from 10 U/ml to 1000 U/ml [0014]. MPEP 2144.05 states “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)”.
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With respect to claims 15-17, Akers et al. teach the zinc binding compound is a citrate including citric acid shown above (p14, line 9-10).
With respect to claim 18, Akers et al. teach the zinc binding compound of citrate at a concentration 10-30 mM (p14, line 9, Cas No.: 77-92-9).
With respect to claim 19, Akers et al. teach citrate concentration is a result effective variable of Zn-binding compound, which can be optimized to about 10 mM to about 35 mM (p14, line 18), reading on a concentration of 40-50 mM. See MPEP 2144.05 (II)(A) "It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior
inventions."
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With respect to claim 20, the molar ratio of zinc to citrate is 2:10 (1:5) to 0.2:30 (1:150) based on the formulation of claim 1 shown as follows.
With respect to claim 21, Akers teach zinc binding of citrate, inherent with logK = 4.95 at 25 °C according to applicant’s admission in specification (p8, last para), optimized to about 10 mM to about 35 mM (p14, line 18) in the insulin formulation.
With respect to claim 22, Akers teach zinc binding of citrate without teaching or suggesting other zinc binding compounds in the formulation, reading on other zinc binding compounds, NOT citrate (logK = 4.95 at 25 °C), less than 0.1 mM having a logK with respect to zinc ion binding of 10-12.3 at 25 °C.
With respect to claims 34-35, Akers et al. teach the insulin formulation further comprises a surfactant in a concentration from about 0.001 (10-5g/ml=10 μg/ml) to about 0.2% (200 μg/ml) w/v (p4, line 10-11; p19, line 21-32). Maggio teaches dodecyl maltoside has been demonstrated to prevent self-association of insulin and thus prevent inactivation of biological activity [0074].
With respect to claims 36, 38, and 40, Akers et al. teach European Pharmacopeial requirement for osmolality is > 240 mOsmol/kg), then a tonicity agent should generally be added to raise the tonicity of the composition to about 300 mOsmol/kg. Typical tonicity agents are glycerol (glycerin) and sodium chloride (p8, line 3-5; p21, line 1-6).
With respect to claim 39, Akers et al. teach an insulin formulation comprising 0.2 mM ZnCl2, 1 mM MgCl2 and 1 mM NaCl as the major chloride resources, the chloride concentration is estimated to be 3.4 mM calculated as (0.2 x 2 + 1 x 2 + 1). Also see the calculation for rejection of claim 1.
With respect to claims 41-42, Akers et al. teach the pH of insulin composition is from about 7.0 to about 7.8 (p8, line 13).
With respect to claim 44, Akers et al. teach the composition further comprising a buffer of sodium phosphate (p8, line 7).
With respect to claim 45, Akers et al. teach preservatives commonly used in insulin products include phenol and m-cresol (p20 line 19-21).
With respect to claim 50,
Akers et al. teach the insulin concentration is a result effective variable and optimized from about 100 to about 500 IU/ml (p13, line 8-9 and claim 3; including a concentration slightly above 500 IU/ml, e.g., 501 IU/ml). Consistently, Bley et al. teach the concentration of insulin analog can be optimized from 10 U/ml to 1000 U/ml [0014].
Akers et al. teach the composition comprising about 0.2 mM to about 2 mM zinc shown as follows (p23, line 16; claim 1). Akers et al. teach 1 unit
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of insulin aspart is equal to 0.035 mg (p12, line 22-23), reading on the limitation (ii) for a weight ratio of 2 mM Zn to 500 IU insulin as 0.74%.
Akers et al. teach the insulin composition comprising about 10 to about 35mM of negatively charged citrate acid able to bind to zinc (p14, line 9, Cas No.: 77-92-9; p14, line 18) and “less than 0.1 mM of any zinc binding species having a logK with respect to zinc ion binding of more than 12.3 at 25 °C” in the first wherein clause.
Akers et al. teach a surfactant, in a concentration from about 0.001 to about 0.2 % w/v (p4, line 10-11), equivalent to 10 μg/ml to about 200 μg/ml (w/v). Akers et al. show the surfactant is a non-ionic surfactant as a trehalose derivative of trehalose laurate ester, an alkyl glycoside, (p19, line 29).
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With respect to the ionic strength in the second wherein clause, Akers’s insulin formulation comprising 0.2 mM Zn, 3 mM Mg, and 1 mM NaCl. The ionic strength of the composition is about 8 mM calculated above. Also see rejection of claims 2-3 above.
With respect to claim 51, Akers et al. teach the insulin composition comprising about 10 to about 35mM of negatively charged citrate acid able to bind to zinc (p14, line 9, Cas No.: 77-92-9; p14, line 18).
With respect to claim 69, Akers et al. show the insulin composition does not contain a vasodilator, nicotinamide, nicotinic acid or a salt thereof (claim 1).
With respect to claims 70-71, Bley et al. teach the insulin aspart formulation further comprising one or more active pharmaceutical ingredients of antidiabetic agent comprising GLP-1 receptor agonists, dual GLP-1 receptor/glucagon receptor agonists, as well as Amylin and amylin analogues [0027; claim 12]. Bley et al. further teach an amylin analogue of pramlintide/Symlin® [0056].
With respect to claim 73, see same rationales for rejecting claims 1, 18, and 20-22.
With respect to claim 80, Akers et al. teach the insulin can be the elected species of insulin aspart (p13, line 5-10).
With respect to claims 81-82, Maggio teaches dodecyl maltoside has been demonstrated to prevent self-association of insulin and thus prevent inactivation of biological activity [0074].
With respect to claims 83-84, Akers et al. teach typical tonicity agents are glycerol (glycerin) and sodium chloride, and glycerol (glycerin) is preferred (p21, line 5-7).
With respect to claim 85, Akers et al. teach the pH of insulin composition is from about 7.0 to about 7.8 (p8, line 13).
With respect to claims 88 and 95, Akers et al. teach “One unit of insulin aspart corresponds to 6 nmol, corresponding with 0.035 mg salt-free anhydrous insulin aspart” (p12,
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line 22-23). At Zn concentrations of 0.2 mM and 2 mM, the weight ratio is calculated to be between 0.074% and 0.74% shown above.
With respect to claim 89, Akers et al. teach citrate concentration is a result effective variable of Zn-binding compound, which can be optimized to about 10 mM to about 35 mM (p14, line 18), reading on a concentration of 40-50 mM.
With respect to claim 90, Akers’s insulin formulation comprising 0.2 mM Zn, 3 mM Mg, and 1 mM NaCl. The ionic strength of the composition is about 8 mM calculated as follows:
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With respect to claims 91 and 93, Akers et al. teach, preferably, the route of insulin administration is by self-administered subcutaneous injection (p22, line 11).
With respect to claims 92 and 94, the limitation “for intramuscular administration” does not change the ingredients of the aqueous liquid insulin formulation; thus, the aqueous liquid insulin formulation taught by Akers et al. in view of Maggio satisfying the limitation for an intended use.
Applicant’s Arguments
The Claims are Nonobvious over Akers in view of Maggio because the reasons as follows:
a person skilled in the art considering Akers would not have had reason to consider 500 U/mL and Akers teaches total chloride concentration ranges from about 10 to about 60 mM are required in its compositions to stabilize insulin (Remarks, p12, para 2-3).
Akers does not disclose the preparation of a single composition that displays "a more rapid uptake of insulin into the blood from the injection site and a more rapid onset of action than existing insulin products, for which it is necessary to add a surfactant in order "to achieve sufficient chemical and physical stability". No alkyl glycoside had been approved by the US FDA for use in a therapeutic (Remarks, p12, last para to p13, para 1-2).
Maggio reports that the intranasal administration of compositions. Maggio does not disclose or suggest that any concentration of DDM. The formulations of Maggio contain significantly lower concentrations of insulin than the compositions of Akers (Remarks, p13, last 2 para to p14, para 1-2).
Maggio contain significantly lower concentrations of insulin than the compositions of Akers (Remarks, p14, para 3).
(b) Akers in view of Maggio does not provide a reason to modify the compositions of Akers so as to arrive at the claimed formulations with a reasonable expectation of success for the reasons as follows:
(i) Dr, Jezek, it was generally understood in field of biochemistry and the formulation of biological solutions on September 29, 2016, that increasing the concentration of insulin/insulin analogues in rapid-acting insulin analogue formulations such as those of Akers, results in an undesirable slower onset of action. Akers would have had no reasonable basis for expecting that the insulin concentration in the formulations of Akers could actually be increased from that of the exemplified formulations (i.e., no more than 110 U/mL) to a concentration of about 500 U/mL and higher (e.g., >500-1,000 U/mL), without reducing the rate of uptake, onset of action, and stability of the composition compared to that demonstrated for Akers's formulations (see, Jezek Declaration, ~33). Maggio discloses the preparation of low concentration insulin (12.2 U/mL Humulin-R) formulations (Remarks, p15, para 2-3).
(ii) Akers discloses that an injected insulin/insulin analogue composition containing citrate at an optimized concentration from about 10 mM to about 30 mM and a total chloride optimized concentration from about 10 mM lo about 60 mM is required to achieve the more rapid uptake of insulin into the blood from the injection site and the more rapid onset of action. Whereas Maggio is silent regarding the time and action profile of an injected insulin formulation. As confirmed by Dr. Jezek, a person of ordinary skill in the art considering Akers in view of Maggio would not have had reason to modify the compositions or teaching of Akers (Remarks, p15, last para to p16, para 1).
(iii) Furthermore, a person of ordinary skill in the art considering Akers in view of Maggio would not have had reason to modify the compositions or teaching of Akers so as to arrive at an aqueous liquid pharmaceutical formulation (Remarks, p16, para 2).
The data presented in Akers suggests that surfactants are not "necessary to achieve sufficient chemical and physical stability" in Akers's formulations. Moreover, Akers does not once mention an alkyl glycoside (Remarks, p16, last para).
Applicant respectfully submits that it cannot reasonably be concluded that a person of ordinary skill in the art considering Akers in view of Maggio would have been motivated to modify the compositions of Akers and would have predictably arrived at the claimed compositions according to Dr. Jezek’s opinions comprising (i) chloride could be replaced or supplemented with acetate and (ii) Akers does not explicitly teach that the total chloride concentration is below the required "about 10 mM," taught in Akers (Remarks, p17, para 2 to p18, para 1-2).
The Patent Office then proceeds to selectively pick and combine particular disclosures of Akers to provide an ad hoc calculation that arrives at a total chloride concentration below 8 mM and attempts to support this calculation with the statement that the disclosure of Akers is relevant for all that it contains (p19, para 2).
Dr. Jezek's testimony which states that the Patent Office's reasoning is flawed
Because Akers’s composition must contain about 10 to about 60 mM total chloride (Remarks, p19, para 3-5 to p20, para 1-2).
Dr. Jezek also testifies that Dr. Jezek points out that the only support provided in Maggio for its general statement in paragraph [00741 that "[dlodecyl rnaltoslde has been demonstrated to prevent self-association of insulin and thus prevent inactivation of biological activity," is the disclosure that compositions containing very low concentrations of insulin (Remarks, p20, last para).
In contrast to Maggio, Akers's formulations contain at least 100 U/mM insulin, do not require EDTA, contain a total chloride concentration from about 10 to about 60 mM, and do not appear to necessarily require a surfactant in order to achieve the time, action and stability profile sought in Akers's compositions (Remarks, p21, para 1).
Akers does not mention an alkyl glycoside and does not appear to require a surfactant or EDTA to achieve more rapid uptake of insulin into the blood from the injection site and more rapid onset of action than existing insulin products. Secondly, the statement in Maggio that "dodecyl maltoside has been demonstrated to prevent self-association of insulin and thus prevent inactivation of biological activity" is conclusory. This general claim finds only limited support in the specific compositions disclosed within Maggio itself (Remarks, p21, para 2).
(c) Affidavit argument (AD relevant statement are included as follows)
Statement 15 (referred to S15): Akers only suggests insulin concentration up to about 500 U/mL (AD p4, last para to p5, para 1).
Statement 16 (S16): Akers discloses that a citrate concentration from about 10 mM to about 30 mM is required to provide the more rapid uptake and onset of insulin action that differentiates its compositions from other insulin products (Remarks, p5, S16).
Statement 17 (S17): In certain embodiments, the total amount of chloride concentration from about 10 mM to about 25 mM (AD, p5, S17).
Statement 19 (S19): Akers does not disclose the preparation of a single composition that displays "a more rapid 1ptake of insulin into the blood from the injection site and a more rapid onset of action than existing insulin products, for which it is necessary to add a surfactant (AD, p6, S19).
Statement 20-21 (S20-S21), Dr. Jazak thinks Akers’ teaching the beneficial combination of surfactant and magnesium is unsupported (AD, p6-7, S20-21).
Statement 22 (S22): Akers does not teach insulin examples comprising surfactant. Akers teaches "total chloride concentration of the disclosed compositions ranges "from about 10 to about 60 mM" (AD, p7, S22).
Statement 23 (S23): Akerss surfactant is limited to parenteral pharmaceutical composition and no alkyl glycoside had been approved for use in a parenterally administered composition, such as an intravenous or intramuscular injection (AD, p7, S23).
Statement 24 (S24): DOM was known to increase the permeability of nasal mucosa, the properties of a surfactant and absorption enhancer in nasal drug delivery systems are not necessarily transferable to injectable formulations without extensive clinical evidence (AD, p7, S24).
Statement 25-26 (S25-26): Maggio’s insulin concentration is lowed than 500 U/ml as claimed (AD, p8, S25-S26).
Statement 27 (S27): Maggio makes the general statement "[c]oncentrated insulin preparations are inactivated by self-aggregation" and that "high protein concentration is problematic in therapeutic formulations" (emphasis added). However, Maggio provides no contextual support for this statement (AD, p8, S27).
Statement 28 (S28): Maggio Paragraph [0074] states"[ d]odecyl maltoside has been demonstrated to prevent self-association of insulin and thus prevent inactivation of biological activity." Is limited to the examples of lower insulin concentration bot not forinsulin concentration at or above 100 U/ml (AD, p8, S28).
Statement 29 (S29): It is my opinion as an expert in the field of biochemistry and the formulation of biological solutions, that a person of ordinary skill in the art on September 29, 2016, would not have had reason to combine the teachings of Akers in view of Maggio because they address fundamentally different problems with fundamentally different solutions (AD, p9, S29).
Statement 30 (S30): Maggio contain significantly lower concentrations of insulin than the compositions of Akers (AD, p9, S30).
Statement 31 (S31): It is my opinion as an expert in the field of biochemistry and the formulation of biological compositions that a person of ordinary skill in the art on September 29, 2016, would not have had reason to modify the compositions or teaching of Akers so as to arrive at the compositions claimed in the '730 Application and would not have reasonably expected to be able to do so (AD, p9, S31).
Statement 32 (S32): The high concentration of insulin as claimed is not for administration by intranasal delivery (AD, p10, S32).
Statement 33 (S33): Akers discloses insulin compositions containing a citrate concentration from about 10 mM to about 30 mM and a total chloride concentration from about 10 to about 60 mM, that are stated to have a more rapid uptake of insulin into the blood from the injection site and a more rapid onset of action than existing insulin products (AD, p10-11, S33).
Statement 34 (S34): Akers discloses that an injected insulin/insulin analogue composition containing citrate at an optimized concentration from about 10 mM to about 30 mM and a total chloride optimized concentration from about 10 mM to about 60 mM is required to achieve the more rapid uptake of insulin into the blood from the injection site whereas Maggio is silent regarding the time and action profile of an injected insulin formulation (AD, p111, S34).
Statement 35 (S35): A person of ordinary skill in the art considering Akers in view of Maggio would not have had reason to modify the compositions or teaching of Akers so as to arrive at an aqueous liquid pharmaceutical formulation claimed in the '730 Application because no reasonable basis for expecting that increasing the insulin/insulin analogue concentration beyond that exemplified in Akers, and reducing the chloride concentration to less than 8 mM (AD, p11, S35).
Statement 36 (S36): Akers in view of Maggio would not have had reason to modify the compositions or teaching of Akers so as to arrive at an aqueous liquid pharmaceutical formulation (AD, p11, S36).
Statement 37 (S37): As discussed above, a person of ordinary skill in the art considering Akers in view of Maggio would have had no reasonable basis for expecting that increasing the insulin/insulin analogue concentration beyond that exemplified in Akers, and reducing the chloride concentration to less than 8 mM (AD, p11-12, S36).
Statement 38 (S38): it cannot reasonably be concluded that a person of ordinary skill in the art considering Akers in view of Maggio would have arrived at the aqueous formulations claimed in the '730 Application with a reasonable expectation of success (AD, p12, S38).
Statement 39 (S39): The complex and unpredictable art that involves compositions containing biological formulations that contain multiple specified components at specified concentrations, wherein the components interact in non-obvious ways, renders routine optimization inapplicable in the context of the subject matter claimed in the '730 Application (AD, p12-13, S39).
Statement 40 (S40): In view of the discussion herein, it is my opinion as an expert in the field of biochemistry and the formulation of biological solutions, that a person of ordinary skill in the a11 on September 29, 2016, would not have considered the teaching of Akers in view of Maggio. (AD, p13, S40)
Statement 43 (S43): The Office's reasoning contradicts the explicit disclosure of Akers and is inconsistent with how a person of ordinary skill in the art would interpret it. Akers clearly states that the disclosed specific optimized concentrations of both citrate and chloride are required to achieve the claimed rapid onset of action and Akers defines the total chloride concentration as ranging "from about 10 to about 60 mM". (AD, p13, S43)
Statement 44 (S44): Patent Office's reliance on Akers's general statement that insulin compositions may crystallize at low temperatures when the chloride concentration is too high (page 17, line 14- 16), to imply that Akers teaches compositions with a chloride concentration below about 10 mM is both unsupported by and inconsistent with the teaching of Akers. (AD, p14, S44)
Statement 45 (S45): Firstly, the Office speculates that chloride could be replaced or supplemented with acetate, thereby reducing its concentration below 10 mM, but this is not taught in Akers. Secondly, the Patent Office's attempt to calculate a total chloride concentration below about 10 mM by selectively picking among and combining particular disclosures of Akers is an ad hoc estimation that misinterprets Akers' s disclosure (p14, S45).
Statement 46 (S46): The Patent Office then proceeds to selectively pick and combine particular disclosures of Akers to provide an ad hoc calculation that arrives at a total chloride concentration below 8 mM (AD, p14-15, S46).
Statement 47 (S47): I point out that the Patent Office's reasoning is flawed because it fails to consider how a person of ordinary skill would interpret the disclosure and teachings of Akers and Maggio (i.e., the disclosure and teaching of Akers and Maggio when viewed in their entireties, as opposed to selective disclosure that can be taken out of context (AD, p15, S47).
Statement 48 (S48): Akers does not exclude the inclusion of other components or concentrations that would result in a total chloride concentration of about l0 mM. It is unreasonable to equate a concentration of "about l0 mM" with one of less than 8 mM (AD, p15, S48).
Statement 49 (S49): I point out that the Patent Office's reasoning fails to take into consideration how a person of ordinary skill would have interpreted the disclosure and teaching of Akers and Maggio (AD, p15, S49).
Statement 50 (S50): A person of ordinary skill in the art, following the explicit instructions and examples of Akers, would have had no reason or motivation to create a formulation with a total chloride concentration below the clearly mandated concentration floor of about 10 mM (AD, p15-16, S50).
Statement 51-52 (S51-52): In response, I point out that the Office's reasoning is inconsistent with how a person of ordinary skill in the art would have interpreted the disclosure of Maggio and its relevance to Akers (AD, p16-17, S51-52).
Statement 53 (S53): Akers's formulations contain at least 100 U/mM insulin, do not require EDTA, contain a total chloride concentration from about 10 to about 60 mM, and do not appear to necessarily require a surfactant in order to achieve the time, action and stability profile sought in Akers's compositions Akers (AD, p17, S53).
Statement 54 (S54): Akers' Background Section (page 3, paragraph 1) refers to a poster indicating that "citrate alone ... is insufficient to improve the [insulin lispro] absorption profile" and that "[b]oth chelation of zinc with EDTA (to hasten disassembly of the less stable insulin analogue hexamer) and citrate (to mask the surface charge and prevent re-aggregation) are required above a threshold concentration to enhance the subcutaneous rate of absorption" (Exhibit O, emphases added). Akers does not mention an alkyl glycoside and does not appear to require a surfactant or EDTA to achieve more rapid uptake of insulin into the blood from the injection site and more rapid onset of action than existing insulin products. Secondly, the statement in Maggio that "dodecyl maltoside has been demonstrated to prevent self-association of insulin and thus prevent inactivation of biological activity" is conclusory (AD, p17, S54).
(d) Akers in view of Maggio further in view of Bley (AD, p17-p20). Statements 55-64 contain substantially the same arguments described above (please find relevant response to argument (a)-(c) above) except for S59 and 60 as follows
Statement 59 (S59): Bley fails to disclose the preparation of a single formulation that contains an insulin concentration of more than 100 U/mL (AD, p18-19, S59).
Statement 60 (S60): Bley, like Akers, proposes that the disclosed composition may further comprise a surfactant as a stabilizing agent and like Akers provides a long list of exemplary surfactants that a person of ordinary skill in the art would recognize to include members that are not interchangeable for the purpose of stabilizing insulin in compositions of 100 U/mL or higher (AD, p19, S60).
Response to Arguments
Applicant's arguments filed 8/13/2025 have been fully considered but they are not persuasive because the arguments do not apply to the modified rejection based on
Akers et al. in view of Bley et al. and evidenced by Humulin R without Maggio discussed as follows.
Applicant’s argument a(i) is not persuasive because (1) Akers et al. teach the insulin concentration is a result effective variable and optimized from about 100 to about 500 IU/ml (p13, line 8-9 and claim 3; including a concentration slightly above 500 IU/ml, e.g., 501 IU/ml), (2) Consistently, Bley et al. teach the concentration of insulin analog can be optimized from 10 U/ml to 1000 U/ml [0014], and (3) Humulin R is further cited to show the common knowledge of using the high concentration of insulin (e.g., RU-500; 500 U/mL) to treat insulin-resistant patients with diabetes requiring daily doses of more than 200 units via subcutaneous administration (p2, Indications and usage) demonstrating the reason to consider 500 U/mL or higher concentration of insulin. Furthermore, Akers et al. teach if chloride may cause crystallization of insulin, reading on aggregation, (p17, line 14-16); thus, one of ordinary skill in the art would minimize the use of chloride in a formulation to avoid aggregation of insulin. Bley et al. teach zinc acetate is a common compound to substitute zinc chloride for insulin formulation known in the art [0017]. When one of ordinary skill in the art to use zinc acetate instead of zinc chloride for stabilizing insulin, the concentration of chloride is as low as 3 mM. See the calculation of chloride concentration in the office action above in details not repeated here. A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989). See MPEP 2123(I).
Applicant’s argument a(ii) is not persuasive because (1) Akers et al. teach the present inventors have surprisingly found that compositions containing certain concentrations of citrate have more rapid uptake of insulin into the blood and/or onset of action than existing commercially available insulin compositions (p3, line 24-26) and (b) Akers et al. teach the insulin formulation beneficially comprising a stabilizing agent of surfactant in combination with magnesium (p19, 16-20). Akers et al. show the surfactant is a non-ionic surfactant as a trehalose derivative of trehalose laurate ester, an alkyl glycoside, (p19, line 29). Thus, one of ordinary skill in the art would have found it obvious to add an alkyl glycoside (e.g., trehalose laurate ester) in combination with magnesium and citrate for stabilizing an insulin formulation. Furthermore, patent examination is based on MPEP not FDA’s approval as argued by applicant.
Applicant’s arguments a(iii)-a(iv) are not persuasive because Maggio is not cited in the modified rejection based on Akers et al. in view of Bley et al. and evidenced by Humulin R.
Applicant’s arguments b(i)-b(x) are not persuasive because Maggio is no longer cited for the modified rejection based on Akers et al. in view of Bley et al. and evidenced by Humulin R. The response to substantially the same arguments of insulin concentration, glycoside surfactant and chloride concentration of b(i)-(iii), (v), and (viii) is addressed above not repeated here. For arguments b(iv), (vi), (vii), (ix), and (x), also see response to arguments a(i)-a(iv) above as well as the modification rejection above not repeated here.
Dr. Jezek’s Affidavit argument (c) statements are not persuasive because (i) many of Dr. Jezek’s opinions are not in compliance with MPEP, (ii) many of Dr. Jezek’s opinions narrowly interpret prior art references by improperly limiting a prior art teachings to explicitly teaching and examples, and (iii) no factual evidence sufficiently supports Dr. Jezek’s opinions in affidavit arguments.
AD-S15 is not persuasive because (a) up to about 500 U/mL including insulin concentration over 500 U/mL and (b) Bley et al. teach the concentration of insulin analog can be optimized from 10 U/ml to 1000 U/ml [0014]. See response to argument a(i) above.
AD-S16-17 are not persuasive. See response to a(i) and chloride concentration calculation as low as 3 mM in the rejection above, not repeated here.
AD-S19-22 is not persuasive because Akers et al. teach the insulin formulation beneficially comprising a stabilizing agent of surfactant in combination with magnesium (p19, 16-20). Akers et al. show the surfactant is a non-ionic surfactant as a trehalose derivative of trehalose laurate ester, an alkyl glycoside, (p19, line 29). See MPEP 716.02(c) “Expected Beneficial Results are Evidence of Obviousness”. Also see the calculation of chloride concentration in the office action above in details not repeated here.
AD-S23 is not persuasive because Akers et al. teach, preferably, the route of insulin administration is by self-administered subcutaneous injection (p22, line 11), reading on not for administration by intranasal delivery. Akers et al. teach the insulin formulation comprising a stabilizing agent of surfactant in combination with magnesium (p19, 16-20). Akers et al. show the surfactant is a non-ionic surfactant as a trehalose derivative of trehalose laurate ester, an alkyl glycoside, (p19, line 29).
AD-S24 is not persuasive because the argument of DOM is not a limitation in the base and rejected claims.
AD-S25-30 are not persuasive because the modified rejection is used on Akers et al. in view of Bley et al. and evidenced by Humulin R without Maggio as argued by Dr. Jezek.
AD-S31 is not persuasive because Dr. Jezek’s opinion is distinct from one of ordinary skill in the art. A person of ordinary skill in the art is well defined as a person of ordinary creativity able to fit the teachings of multiple patents together like pieces of a puzzle.” Id. 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 ___, 82 USPQ2d at 1396. See MPEP 2141.03 (I). Under this definition, one of ordinary skill in the art would have found the combination of Akers et al. in view of Bley et al. and evidenced by Humulin R without Maggio (by fitting the teachings of multiple patents together like pieces of a puzzle) is obvious to the rejected claims described above not repeated here.
AD-S32 is not persuasive because AD-32 is in agreement with the prior art teaching and common knowledge cited in the prior art references. Humulin R is further cited to show the common knowledge of using the high concentration of insulin (e.g., RU-500; 500 U/mL) to treat insulin-resistant patients with diabetes requiring daily doses of more than 200 units via subcutaneous administration (p2, Indications and usage).
AD-S33 is not persuasive because Akers et al. teach the insulin composition comprising about 10 to about 35mM of negatively charged citrate acid able to bind to zinc (p14, line 9, Cas No.: 77-92-9; p14, line 18). The response to repeated argument of chloride concentration can be found at various places described above, not repeated here.
AD-S34 is not persuasive. See response to argument AD-S33. Furthermore, Maggio is not cited for the modified ejection.
AD-S35-38 are not persuasive because the arguments are not applied to Akers et al. in view of Bley et al. and evidenced by Humulin R without Maggio.
AD-S39 are not persuasive because one of ordinary skill in the art would follow the teachings of Akers et al. in view of Bley et al. and evidenced by Humulin R found it obvious to formulate insulin of 500-1000 U/mL with zinc acetate, citric acid and an alkyl glycoside surfactant in combination magnesium by simply fitting the teachings of cited references together like pieces of a puzzle. See MPEP 2141.03 (I).
AD-S40 is not persuasive because the argument does not apply to the teachings of Akers et al. in view of Bley et al. and evidenced by Humulin R.
AD-S43 is not persuasive because Akers et al. teach if the total chloride content of the composition is too high, the insulin in the composition may crystallize (reading on aggregation) at low temperatures (p17, line 14-16); thus, one of ordinary skill in the art would minimize the use of chloride in a formulation to avoid aggregation of insulin. Bley et al. teach zinc acetate is a common compound to substitute zinc chloride for insulin formulation known in the art [0017]. When 0.2 mM ZnCl2 is replaced by Zn-(acetate)2, the chloride concentration is even lower to 3 mM, far less than 8 mM chloride as claimed. See MPEP 2144.05. 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, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).
AD-S44-46, 48, and 50 are not persuasive. The response to repeated argument of chloride concentration can be found at multiple places described above, not repeated here.
AD-47, 49, and 51-52 are not persuasive because the arguments are not applied to Akers et al. in view of Bley et al. and evidenced by Humulin R without Maggio.
AD-53-54 are not persuasive the transient language “comprising” in line 1 of claim 1 is an open language without limiting any other ingredients in the formulation and EDTA is not a limitation in the rejected claims. Thus, AD-53 is groundless by (1) arguing a limitation of EDTA not in the claims and (2) arguing Maggio not used for the rejection. In particular, there is no evidence the insulin formulation of the background art is the same as Akers’s insulin formulation. On the other hand, Akers et al. clearly teach certain concentrations of citrate have more rapid uptake of insulin into the blood and/or onset of action than existing commercially available insulin compositions (p3, line 24-26). See MPEP 2121(I) When the reference relied on expressly anticipates or makes obvious all of the elements of the claimed invention, the reference is presumed to be operable. Akers et al. teach the insulin formulation beneficially comprising a stabilizing agent of surfactant in combination with magnesium (p19, 16-20). Akers et al. show the surfactant is a non-ionic surfactant as a trehalose derivative of trehalose laurate ester, an alkyl glycoside, (p19, line 29). The benefit of adding an alkyl glycoside surfactant and calculation of chloride concentration have been addressed and can be found at various paragraphs above, not repeated here.
AD-S55-58 and 61-64 contain substantially the same arguments that have been responded above. Applicant can find relevant response above, not repeated here.
AD-S59 is not persuasive because the primary reference of Akers et al. teach the insulin concentration is a result effective variable and optimized from about 100 to about 500 IU/ml (p13, line 8-9 and claim 3; including a concentration slightly above 500 IU/ml, e.g., 501 IU/ml). Consistently, Bley et al. teach the concentration of insulin analog can be optimized from 10 U/ml to 1000 U/ml [0014]. A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989). SEE MPEP 2123(I).
AD-60 is not persuasive because a reference that clearly names the claimed species anticipates the claim no matter how many other species are named. In the present case, Akers et al. show the surfactant is a non-ionic surfactant of trehalose laurate ester, an alkyl glycoside, (p19, line 29). See MPEP 2131.02(II).
Examiner’s comments:
A non-persuasive argument is non-persuasive no matter how many times for repeating substantially the same arguments. Applicant may expect the examiner to maintain the rejection in response to substantially the same arguments above in the next office action.
2. Claims 1-3, 5, 7, 10-11, 15-22, 34-36, 38-42, 44-45, 50-51, 69-71, 73, 80-85, and 88-95 are rejected under 35 U.S.C. 103 as being unpatentable over Akers et al. in view of Bley et al. and evidenced by Humulin R as applied to claims 1-3, 5, 7, 10-11, 15-22, 34-36, 38-42, 44-45, 50-51, 69-71, 73, 80-85, and 88-95 and further in view of Smith et al. (Archives of Disease in Childhood 1991; 66: 879-882, previously cited 8/13/2024).
Claims 92 and 94 are drawn to the insulin formulation is for intramuscular administration.
Akers et al. in view of Bley et al. and evidenced by Humulin R teach a liquid formulation of insulin for subcutaneous injection as applied to claims 1-3, 5, 7, 10-11, 15-22, 34-36, 38-42, 44-45, 50-51, 69-71, 73, 80-85, and 88-95.
Akers et al. in view of Bley et al. and evidenced by Humulin R do not specify the same formulation of insulin for subcutaneous also for intramuscular administration.
Smith et al. teach the same formulation of insulin can be used for either subcutaneous injection or intramuscular injection by changing the angle of injection, not for intranasal injection/delivery (Abstract). Thus, the liquid formulation of insulin taught by Akers et al. in view of Maggio can be used for either subcutaneous injection or intramuscular injection, reading on claims 92 and 94.
One of ordinary skill in the art before the effective filing date of this invention would have found it obvious to combine Akers et al. in view of Bley et al. and evidenced by Humulin R with Smith’s teaching of injection angle because (a) Akers et al. in view of Bley et al. and evidenced by Humulin R teach a liquid insulin formulation for subcutaneous injection and (b) Smith et al. teach the same formulation of insulin can be used for either subcutaneous injection or intramuscular injection by changing the angle of injection (Abstract). The combination would have reasonable expectation of success because all references teach subcutaneous injection of insulin.
Applicant’s Arguments
The claims are Nonobvious over Akers in view of Maggio and Smith because Smith does not cure the deficiencies of Akers in view of Maggio. Smith discloses that the same formulation of insulin can be used for either subcutaneous injection or intramuscular injection by changing the angle of injection in Remarks (p24, para 2 to p26, para 1-2) and AD (p20, S65 to p22, S74)
Response to Arguments
Applicant's arguments filed 8/13/2025 have been fully considered but they are not persuasive because the arguments do not apply to the modified rejection based on
Akers et al. in view of Bley et al. and Simth et al. and further evidenced by Humulin R without Maggio. The arguments are mainly based on Akers in view of Maggio, but Maggio is not cited for the rejection. See response to arguments above.
3. Claims 1-3, 5, 7, 10-11, 15-22, 24-26, 34-36, 38-42, 44-45, 50-51, 69-71, 73, 80-85, and 88-95 are rejected under 35 U.S.C. 103 as being unpatentable over Akers et al. in view of Bley et al. and evidenced by Humulin R as applied to claims 1-3, 5, 7, 10-11, 15-22, 34-36, 38-42, 44-45, 50-51, 69-71, 73, 80-85, and 88-95 and further in view of Maggio (US 2008/0194461 A1, previously cited 11/20/2023).
Claim 24 is drawn to an alkyl glycoside surfactant is the elected species of dodecyl maltoside.
Akers et al. in view of Bley et al. and evidenced by Humulin R teach an insulin formulation comprising an alkyl glycoside surfactant as applied to claims 1-3, 5, 7, 10-11, 15-22, 34-36, 38-42, 44-45, 50-51, 69-71, 73, 80-85, and 88-95.
Akers et al. in view of Bley et al. and evidenced by Humulin R do not specify an alkyl glycoside surfactant as dodecyl maltoside.
Similarly, Maggio teaches beneficial use of an alkylglycoside for increasing the stability, reducing the aggregation and immunogenicity, increasing the biological activity, and reducing or preventing fibrillar formation of a peptide for insulin formulation (Abstract) as insulin is well known to lose activity rapidly as a result of protein aggregation upon agitation at temperatures above those found upon refrigerated storage [0005]. Maggio teaches alkylglycoside of the invention includes but is not limited dodecyl maltoside, tridecyl maltoside, tetradecyl maltoside, sucrose mono-dodecanoate, sucrose mono-tridecanoate, and sucrose mono-tetradecanoate [0011]. Maggio teaches the insulin formulation comprising alkylglycoside is suitable for injection routes including subcutaneous, intravascular, or intravenous administration, not limited to nasal administration [0053, 0124, 0129]. Maggio shows insulin formulation retain insulin activity of lowering glucose level in the presence of dodecyl maltoside (DDM) or sucrose dodecanoate (SDD) compared to the absence of alkylglycoside in an insulin formulation shown as follows [0136, Table 5]. Table IV further shows higher dose of 0.18% DDM is more effective than 0.125% DDM to retain insulin activity of lowering glucose
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level, demonstrating DDM is beneficial to retain insulin activity for subcutaneous, intravascular, or intravenous injection and as well as other routes taught by Maggio [0053, 0124, 0129]. Because Maggio shows insulin formulation retain insulin activity of lowering glucose level in the presence of dodecyl maltoside surfactant (DDM) for subcutaneous, intravascular, or intravenous injection, one of ordinary skill in the art would have found it obvious to add Maggio’s dodecyl maltoside surfactant (DDM) in a insulin formulation taught by Akers et al. in view of Bley et al. and evidenced by Humulin R for subcutaneous, intravascular, or intravenous injection, reading on claims 24-26 and 91-94.
One of ordinary skill in the art before the effective filing date of this invention would have found it obvious to combine (i) Akers et al. in view of Bley et al. and evidenced by Humulin R and (ii) Maggio’s alkylglycoside of dodecyl maltoside (DDM) because (a) Akers et al. in view of Bley et al. and evidenced by Humulin R teach an insulin formulation comprising an alkyl glycoside surfactant (p19, line 29) and (b) Maggio teaches beneficial use of an alkylglycoside for increasing the stability, reducing the aggregation and immunogenicity, increasing the biological activity, and reducing or preventing fibrillar formation of a peptide for insulin formulation (Abstract) as insulin is well known to lose activity rapidly as a result of protein aggregation upon agitation at temperatures above those found upon refrigerated storage [0005]. Maggio shows insulin formulation retain insulin activity of lowering glucose level in the presence of dodecyl maltoside (DDM) or sucrose dodecanoate (SDD) compared to the absence of alkylglycoside in an insulin formulation [0136, Table 5]. The combination would have reasonable expectation of success because both Akers et al. and Maggio teach beneficial addition of an alkylglycoside surfactant in an insulin formation suitable for subcutaneous injection.
Response to Arguments
Applicant's arguments filed 8/13/2025 have been fully considered but they are not persuasive because the arguments do not apply to the modified rejection based on Akers et al. in view of Bley et al., evidenced by Humulin R and further in view of Maggio. In particular, both Akers et al. and Maggio teach beneficial addition of an alkylglycoside surfactant in an insulin formation suitable for subcutaneous injection; whereas, applicant mistakenly argues (i) Akers et al. do not teach alkylglycoside in formulation of insulin, (ii) Maggio did not teach subcutaneous injection of insulin, and (iii) an alkylglycoside can only be used for low concentration of insulin not for insulin of 500 U/ml without data support. Furthermore, Dr. Jezek’s Affidavit opinions deviated from the fact taught by cited references above without data support do not represent one of ordinary skill in the art able to fit the teachings of multiple patents together like pieces of a puzzle as defined in MPEP 2141.03 (I).
Modified Rejection
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 1-3, 5, 7, 10-11, 15-22, 24-26, 34-36, 38-42, 44-45, 50-51, 69-71, 73, 80-85, and 88-95 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 5, 10-11, and 13-18 of U.S. Patent No. US 11,278,624 B2 (the ‘624 patent) in view of Akers et al. (WO 2016/100042 A1, previously cited 8/13/2024) in view of Bley et al. (US 2015/0190475), Maggio (US 2008/0194461 A1, previously cited 8/13/2024) and further evidenced by Humulin R (Lilly USA, LLC 2011).
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Claim 1 of the ‘624 patent show the formulation without chloride. The specification disclosed a preferred zinc binding species of citrate with logK = 4.95 at 25 °C, (p8, last para), reading on the limitation (iii). The specification of the ‘624 patent disclosed the insulin analog encompassing aspart (col 10, line 61). The specification of the ‘624 patent further disclosed the route of administering the insulin encompassing subcutaneous and intramuscular injection (col 10, line 16-18).
Claim 1 of the ‘624 patent does not show the insulin formulation further comprising an alkyl glycoside at a concentration of 10-200 μg/ml.
The relevancy of Akers et al. in view of Bley et al., Maggio and further evidenced by Humulin R as applied to claims 1-3, 5, 7, 10-11, 15-22, 24-26, 34-36, 38-42, 44-45, 50-51, 69-71, 73, 80-85, and 88-95 not repeated here.
Because Akers et al. in view of Bley et al., Maggio and further evidenced by Humulin R teach beneficial addition of alkyl glycoside surfactant in formulation of an insulin, one of ordinary skill in the art would have found it obvious to combine the insulin formulation taught by claim 1 of the ‘624 patent in view of Akers et al., Bley et al., Maggio and further evidenced by Humulin R.
Thus, claim 1 of the ‘624 patent in view of Akers et al., Bley et al., Maggio and further evidenced by Humulin R. are obvious to the instant claims 1-3, 5, 7, 10-11, 15-22, 24-26, 34-36, 38-42, 44-45, 50-51, 69-71, 73, 80-85, and 88-95.
Claim 3 of the ‘624 patent disclosed the insulin is insulin aspart, satisfying the instant claims 5 and 7.
Claim 1 of the ‘624 patent disclosed an insulin analogue at a concentration of 100-1000 U/ml, satisfying the instant claims 10-11.
Claim 1 of the ‘624 patent disclosed the zinc binding species is 10-50 mM citrate as a chelating agent, reading on citric acid, satisfying the instant claims 15-18.
Claim 16 of the ‘624 patent disclosed the zinc binding citrate is present at a concentration of 30-50 mM, satisfying the instant claims 19, 51, and 89.
Claim 18 of the ‘624 patent disclosed the molar ratio of ionic zinc to citrate as chelating agent is in the range 1:20-1:100, satisfying the instant claim 20.
Claim 1 of the ‘624 patent disclosed the zinc binding species of citrate is 10-50 mM, satisfying the instant claim 21.
Claim 1 of the ‘624 patent disclosed the composition does not contain any zinc binding species having a logK with respect to zinc ion binding of more than 12.3 at 25°C, satisfying the instant claim 22.
Claim 1 of the ‘624 patent disclosed a non-ionic surfactant at a concentration 0.05-0.5 mg/m (50-500 µg/ml), satisfying the instant claims 34-35.
Claim 10 of the ‘624 patent disclosed tonicity modifiers consisting of trehalose, mannitol, glycerol or 1,2-propanediol, satisfying the instant claim 36.
Claim 11 of the ‘624 patent disclosed tonicity modifier as glycerol, satisfying the instant claims 38 and 83-84.
Claim 1 of the ‘624 patent disclosed the composition does not contain chloride, satisfying the instant claim 39.
Claim 13 of the ‘624 patent disclosed the pH is in the range 5.5 to 9.0, satisfying the instant claim 41.
Claim 14 of the ‘624 patent disclosed the pH is in the range 7.0 to 7.5, satisfying the instant claims 42 and 85.
Claim 15 of the ‘624 patent disclosed the pH is in the range 7.6 to 8.0, satisfying the instant claim 42.
Claim 17 of the ‘624 patent disclosed the composition comprising a preservative selected from phenol, m-cresol, chlorocresol, benzyl alcohol, propylparaben, methylparaben, benzalkonium chloride and benzethonium chloride, satisfying the instant claim 45.
Claim 1 of the ‘624 patent disclosed the formulation which does not contain a vasodilator, nicotinamide, nicotinic acid or a salt thereof, satisfying the instant claim 69.
Claim 5 of the ‘624 patent disclosed the zinc is present at a concentration of 0.35-0.75% by weight of zinc based on the weight of insulin analogue, satisfying the instant claim 88.
Response to Arguments
Applicant's arguments filed 8/13/2025 have been fully considered but they are not persuasive because applicant’s request this ODP held in abeyance until allowable subject matter is found does not overcome the rejection of record.
Claims 1-3, 5, 7, 10-11, 15-22, 24-26, 34-36, 38-39, 41-42, 45, 50-51, 69-71, 73, 80-85 and 88-94 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 12,527,845 B2 (the ‘845 patent, previously rejected as copending Application No. 16/337,706) in view of Akers et al. (WO 2016/100042 A1, previously cited 8/13/2024) in view of Bley et al. (US 2015/0190475), Maggio (US 2008/0194461 A1, previously cited 8/13/2024) and further evidenced by Humulin R (Lilly USA, LLC 2011).
Claim 1 of the ‘845 patent disclosed an insulin formulation absence of chloride.
Claim 1 of the ‘845 patent did not disclosed the insulin concentration as 500 U/ml or above.
The relevancy of Akers et al. in view of Bley et al., Maggio and further evidenced by Humulin R as applied to claims 1-3, 5, 7, 10-11, 15-22, 24-26, 34-36, 38-42, 44-45, 50-51, 69-71, 73, 80-85, and 88-95 not repeated here.
Because Akers et al. in view of Bley et al., Maggio and further evidenced by Humulin R teach beneficial use high concentration of insulin to treat insulin-resistant patients, one of ordinary skill in the art would have found it obvious to modify the insulin formulation taught by claim 1 of the ‘845 patent in view of Akers et al., Bley et al., Maggio and further evidenced by Humulin R.
Thus, claim 1 of the ‘845 patent in view of Akers et al., Bley et al., Maggio and further evidenced by Humulin R are obvious to the instant claims 1-3, 5, 7, 10-11, 15-22, 24-26, 34-36, 38-42, 44-45, 50-51, 69-71, 73, 80-85, and 88-95.
Response to Arguments
Applicant's arguments filed 8/13/2025 have been fully considered but they are not persuasive because applicant’s request this ODP held in abeyance until allowable subject matter is found does not overcome the rejection of record.
New Ground of Rejection
Claims 1-3, 5, 7, 10-11, 15-22, 24-26, 34-36, 38-39, 41-42, 45, 50-51, 69-71, 73, 80-85 and 88-94 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 and 6 of copending Application No. 16/610,826 (the ‘826 application dated 2025-02-28) in view of Akers et al. (WO 2016/100042 A1) in view of Bley et al. (US 2015/0190475), Maggio (US 2008/0194461 A1) and further evidenced by Humulin R (Lilly USA, LLC 2011).
Claim 1 of the ‘826 application disclosed an insulin formulation without chloride.
Claim 2 of the ‘826 application disclosed the insulin compound is insulin lispro or insulin aspart.
Claim 6 of the ‘826 application disclosed the insulin at a concentration of 10-1000 U/ml.
Claims 1-2 and 6 of the ‘826 application dis not disclosed the alkyl glycoside as dodecyl maltoside (DDM).
The relevancy of Akers et al. in view of Bley et al., Maggio and further evidenced by Humulin R as applied to claims 1-3, 5, 7, 10-11, 15-22, 24-26, 34-36, 38-42, 44-45, 50-51, 69-71, 73, 80-85, and 88-95 not repeated here.
Because Akers et al. in view of Bley et al., Maggio and further evidenced by Humulin R teach beneficial use the alkyl glycoside as dodecyl maltoside in an insulin formulation, one of ordinary skill in the art would have found it obvious to modify the insulin formulation taught by claims 1-2 and 6 of the ‘826 application in view of Akers et al., Bley et al., Maggio and further evidenced by Humulin R.
Thus, claims 1-2 and 6 of the ‘826 application in view of Akers et al., Bley et al., Maggio and further evidenced by Humulin R are obvious to the instant claims 1-3, 5, 7, 10-11, 15-22, 24-26, 34-36, 38-42, 44-45, 50-51, 69-71, 73, 80-85, and 88-95.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claim is allowed.
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/J.L/Examiner, Art Unit 1658
10-February-2026
/LI N KOMATSU/ Primary Examiner, Art Unit 1658