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 .
Priority
This application was filed on and is a U.S. national Stage application under 35 U.S.C. 371 of International Patent Application No. PCT/EP2020/066371 filed 06/12/2020, which claims the benefit of the priority of European Patent Application No. EP19183317.7 filed 06/28/2019.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Claim Status
Claims 22-24, 28, 32, and 38-39 are pending. Claims 22 is amended. Claims 1-21, 25-27, 29-31, 33-37, 40-43 are canceled. Claims 22-24, 28, 32, and 38-39 are being examined on the merits in this office action.
Claim Rejections - Withdrawn
The rejection of claims 28 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is withdrawn in view of applicant’s arguments.
Claim Rejections - 35 USC § 112 - Maintained
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 22, 24, 28, 32, and 38-39 are still rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of lowering hyperglycemia in T1D, does not reasonably provide enablement for a compound used to prevent or for prophylactic treatment of T1D. Examiner notes that the instant application discloses that "treating", "treated" or "treatment" as used herein includes preventative (e.g. prophylactic), palliative, and curative uses or results (Instant Disclosure Page 6, line 20-21). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. This is a scope of enablement rejection.
To be enabling, the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1561 (Fed. Cir., 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558,1564 (Fed. Cir. 1996).
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls. 1986) at 547, the court recited eight factors to consider when assessing whether or not a disclosure would require undue experimentation. These factors are:
1) the quantity of experimentation necessary
2) the amount of direction or guidance provided
3) the presence or absence of working examples
4) the nature of the invention
5) the state of the art
6) the relative skill of those in the art
7) the predictability of the art
8) the breadth of the claims.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099,1108,427 F.2d 833, 839,166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
The breadth of the claims and the nature of the invention
The invention is drawn to a method of treating type 1 diabetes, in a subject in need thereof, the method comprising administering to the subject a therapeutically- effective amount of: (i) a recombinant S100 calcium-binding protein A9 (S100A9 protein), and (ii) insulin.
Examiner notes that the instant application discloses that "treating", "treated" or "treatment" as used herein includes palliative, and curative uses or results (Instant Disclosure Page 6, line 20-21). Examiner notes that palliative which includes treating associated symptoms of the disease and includes curing T1D. Therefore, the instant method includes curing T1D.
The instant specification is bereft of evidence of curing of T1D. The specification does not demonstrate the efficacy of the elected method in curing T1D in general. Since absolute success in curing T1D is not reasonably possible based on the state of the art at the earliest effective filing date of the instant application, the specification, which lacks an objective showing that T1D can be actually cured, is viewed as lacking.
The state of the prior art and the level of predictability in the art and the relative skill of those in the art
The state of the art is such that there is evidence and established literature that T1D cannot be prevented. It is known in the art that T1D cannot be prevented (CDC- Type 1 Diabetes | Diabetes | CDC). Further, University of Rochester medicine (Can Type 1 Diabetes Be Cured? Diabetes Myths Debunked | University of Rochester Medicine) discloses that T1D is an autoimmune diseases which can only be managed but cannot be cured (Page 2).
Given that there is no evidence in the art of a compound that has been found to generally cure and prevent T1D, the method of preventing and curing T1D is not considered enabled.
One of ordinary skill in the art would not be able to use the claimed invention to cure and prevent T1D and achieve a reasonable level of success in doing so due to the absence in the art of a compound that is able to cure and prevent T1D. It is well established that a utility rejection is therefore proper when the scope of enablement is not reasonably correlated to the scope of the claim.
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation’.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)”. The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” As a result, the specification needs to have more details on how to make and use the invention in order to be enabling. The relative skill of those in the art is high. However, the art of T1D prevention is highly unpredictable.
The teachings from CDC and University of Rochester medicine show how unpredictable the prevention and cure of T1D is generally. Considering the state of the prior art, it is apparent that the instantly claimed method is not capable for use to prevent and cure T1D.
The amount of direction or guidance provided and the presence or absence of working examples
The claims are drawn to a method of treating type 1 diabetes, in a subject in need thereof, the method comprising administering to the subject a therapeutically- effective amount of: (i) a recombinant S100 calcium-binding protein A9 (S100A9 protein), and (ii) insulin. Examiner notes that the instant application definition of treating includes palliative and curing. The instant Examples disclose that the method was successful in ameliorating metabolic imbalance in insulin deficiency mice such as reducing hyperglycemia (Fig 1-4). The instant specification does not include other examples showing effect of the claimed method in preventing and curing T1D.
The quantity of experimentation necessary
Given the well-known unpredictability of the art as well as the incomplete experimental evidence commensurate in scope with the claims, the skilled artisan would not be able to agree that the claimed method can cure T1D. To determine if the claimed method can cure T1D, the suitable dosage as well as clinical trials or assays that can correlate to clinical efficacy of such treatment would be needed. This is undue experimentation given the limited guidance and experimentation provided by the applicant.
In view of the Wands factors discussed above, to practice the claimed invention herein, a person of skill in the art would have to engage in unduly burdensome experimentation to assess whether administration of the claimed S100A9 protein and insulin would cure and prevent T1D. Thus, the rejection of these claims under 35 USC 112(a) is proper.
Response to Arguments
Applicant's arguments filed 09/01/2026 have been fully considered but they are not persuasive.
Applicant argues that the specification has been amended to remove preventative or prophylactic use from the definition of treating (Page 5 of Arguments).
The arguments presented above have been fully considered but are unpersuasive. Examiner notes that Applicant is enabled for a method of lowering hyperglycemia in T1D and not a method of treating diabetes. Examiner notes that the instant application discloses that "treating", "treated" or "treatment" as used herein includes palliative, and curative uses or results. However, the Examiner indicated that the state of the art discloses that T1D is an autoimmune disease which can only be managed but cannot be cured (Page 2). Given that there is no evidence in the art of a compound that has been found to generally cure and prevent T1D, the method of preventing and curing T1D is not considered enabled. As a result, this rejection is maintained.
Claim Rejections - 35 USC § 103 – Maintained
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 22-24, 28, 32, and 38-39 are rejected under 35 U.S.C. 103 as being unpatentable over Ortega et al. (J Mol Med (2013) 91:523–534) in view of Jarvinen et al. (Diabetes Care 2001;24(4):758–767), Tang et al. (WO2005049806A2 – hereinafter “Tang”) and Mu et al. (WO2017205191A1 – hereinafter “Mu”).
Ortega teaches that a genetic variation for S100A9 gene, associated with increased S100A9 levels, was also associated with a lower risk of T2D (Page 531, right col., line 12-13). S100A9 may be positively associated with increased insulin-stimulated glucose uptake in some tissues and cells (Page 531, right col., last sentence). Ortega teaches that S100A9 is able to inhibit zinc-dependent enzymes which are involved in angiogenesis and inflammation, which in adipose tissue are common features of metabolic disturbances and obesity. Finally, S100A9 has antimicrobial activity, including oxidant scavenging and chemokine-like activities, which are of special importance in insulin resistance and T2D. Therefore, circulating and S100A9 gene expressions may be upregulated to counterbalance the increase in inflammatory factors and the molecular modifications in S100A9 that characterizes this condition (Page 32, right col., line 1-11). Ortega teaches using recombinant S100A9 (Page 524, left col., line 4-6; Page 524, left col., line 22; page 526, left col., 3rd paragraph). Examiner notes that the teachings of Ortega disclose that S100A9 can be used to treat T2D and T2D is an example of an insulin deficiency condition.
Ortega does not teach a method wherein the subject is administered both S100A9 and insulin and does not teach the sequences of SEQ ID NO: 1, 7, or 8.
Jarvinen teaches combination therapies with insulin in treating T2D (Title). Jarvinen teaches that long-acting insulin is insufficient to control fasting glycemia in most type 2 diabetic patients (Page 758, left col., 2nd paragraph, line 12-14). Jarvinen teaches that glycemic control is better during insulin combination therapy and that insulin can be lowered to about 30% (Page 758, right col., line 3-15).
Regarding the sequence of S100A9, Tang teaches polypeptides of SEQ ID NO: 653 (claim 20), which is 100%identical to the instant SEQ ID NO: 1. Tang teaches the use of the polypeptides for treating conditions including type 1 diabetes (Page 23, 1st paragraph, line 3).
Regarding the insulin sequences, Mu teaches combination treatment of insulin and GLP-1 analogues for the treatment of diabetes (Abstract) including type 1 diabetes (claim 22). Mu teaches that the insulin and GLP-1 analogue are administered non-simultaneously or simultaneously (Page 21, line 1-4). Mu teaches that the insulin has the sequence of SEQ ID NO: 1 and SEQ ID NO: 2 (Page 27, line 24-29) which are identical to the instant SEQ ID NO: 7 and 8. Mu teaches that the insulin and GLP-1 analogue can be formulated into a single composition, and they can be conjugated. Examiner notes this reads on the same peptide. Mu teaches that the combination treatment exhibits beneficial properties, for example, the ability to cause significant body weight to decrease while having a beneficial effect on glucose control without any evidence of increasing liver weight, e.g., due to fat deposition on the liver (Page 2, line 18-21).
Examiner notes that the instant application discloses that "treating", "treated" or "treatment" as used herein includes palliative, and curative uses or results and palliative uses includes associated symptoms of the disease. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Ortega and Jarvinen and treat insulin deficiency disorder such as T2D with combination therapy of insulin and another agent such as S100A9 since Jarvinen teaches that glycemic control is better during insulin combination therapy (Page 758, right col., line 3-15. It would have been obvious to use the S100A9 and insulin sequence of SEQ ID NO: 1, 7 or 8 as taught by Tang and MU, since both references teach using the peptides for treating diabetes. One of ordinary skill in the art would be motivated and would have had a reasonable expectation of success in treating an insulin deficiency disorder or its associated symptom with a combination therapy of S100A9 and insulin since Jarvinen suggests combination therapy with insulin and Ortega teaches that A100A9 has been used to treat T2D. Examiner notes that the disclosures render obvious claims 22 and 28.
Regarding claim 23, Ortega teaches that that S100A9 decreased fasting triglyceride concentrations (Page 529, left col., line 1-5). Ortega further teaches that recombinant S100A9 had an effect in weight loss and reduced glycated hemoglobin (Page 524, left col., line 1-20). Further, Jarvinen teaches that insulin led to a decrease in triglycerides (Page 761, right col., last paragraph). It would have been obvious to one of ordinary skill in the art to combine the administration of insulin and S100A9 for reducing triglycerides.
Regarding claim 24, Jarvinen teaches that glycemic control is better during insulin combination therapy and that insulin can be lowered to about 30% (Page 758, right col., line 3-15). It would have been obvious to one of ordinary skill in the art to combine the administration of insulin and S100A9 for treating an insulin deficiency disorder so as to reduce the insulin dose.
Regarding claim 32, Jarvinen teaches the use of basal-bolus–type insulin (Page 763, middle col., last sentence). It would have been obvious to treat T2D with a combination of S100A9 and basal insulin as taught by Jarvinen for added glycemic effect.
Regarding claim 38, Jarvinen teaches that insulin and sulfonylurea were administered at bedtime (Page 762, right col., line 8-10), which reads on concomitant administration. It would have been obvious to treat T2D with a combination of S100A9 and basal insulin and administer them concomitantly for added glycemic effect.
Regarding claim 39, Jarvinen teaches that the insulin may be administered with metformin (Page 758, middle col., last two lines; Page 758, right col., last two lines). Examiner notes that biguanide is also known as metformin. It would have been obvious to include other TD2 treatment agents such as metformin for added glycemic control.
Response to Arguments
Applicant's arguments filed 09/01/2026 have been fully considered but they are not persuasive.
Applicant arguments
Applicant argues that claim 22 has been amended and that Ortega does not teach S100A9 and insulin to treat T1D and that Applicant is not claiming any insulin deficiency condition, but specifically T1D (Page 6-7 of Arguments).
Applicant further argues that Tang is a generic and there is no teaching to guide one skilled in the art to select SEQ ID NO: 653 to treat T1D. applicant argues that Mu does not teach insulin and S100A9 for treating T1D (Page 7 of Arguments).
Examiner’s Response
The arguments presented above have been fully considered but are unpersuasive. Examiner notes that the instant application discloses that "treating", "treated" or "treatment" as used herein includes palliative, and curative uses or results. Palliative uses include associated symptoms of the disease all which are taught by the cited references. Examiner notes that Ortega indeed teaches recombinant S100A9 (Page 524, left col., line 4-6; Page 524, left col., line 22; page 526, left col., 3rd paragraph). Ortega teaches that a genetic variation for S100A9 gene, associated with increased S100A9 levels, was also associated with a lower risk of T2D and insulin resistance (Page 531, right col., line 12-13). Examiner further notes that combination therapy with insulin is preferred to control diabetes as taught by Jarvinen. Specifically, Jarvinen teaches combination therapies with insulin in treating T2D (Title). Jarvinen teaches that long-acting insulin is insufficient to control fasting glycemia in most type 2 diabetic patients (Page 758, left col., 2nd paragraph, line 12-14). Jarvinen teaches that glycemic control is better during insulin combination therapy and that insulin can be lowered to about 30% (Page 758, right col., line 3-15). One of ordinary skill in the art would be motivated to use S100A9 in combination with insulin to treat diabetes and would have had a reasonable expectation of success. Examiner notes that indeed insulin resistance is an associated with type 1 diabetes (See Priya et al. (Diabetes Ther. 2017 Nov 14;9(1):349–361)). Ortega teaches that increased S100A9 levels, was also associated with a lower risk of T2D and insulin resistance. Further, Examiner adds that Ortega teaches that S100A9 was also associated with a decrease in triglycerides which is also associated symptom of T1D. Examiner further notes that the instant invention discloses that the invention is focused on treating insulin deficiency conditions and that the condition includes T1D and T2D (Instant Disclosure Page 7, line 1-2). The arguments are unpersuasive.
Examiner notes that while Tang teaches several polypeptides, one of the polypeptide is SEQ ID NO: 653 (claim 20), which is 100%identical to the instant SEQ ID NO: 1. Tang teaches the use of the polypeptides for treating conditions including type 1 diabetes (Page 23, 1st paragraph, line 3). Additionally, the arguments regarding Mu is unpersuasive since Mu teaches combination treatment of insulin and GLP-1 analogues for the treatment of diabetes (Abstract) including type 1 diabetes (claim 22). Mu teaches that the insulin and GLP-1 analogue are administered non-simultaneously or simultaneously (Page 21, line 1-4). Examiner notes that Ortega already teaches that S100A9 can be used to treat to treat diabetes and its associated symptoms. Jarvinen teaches that glycemic control is better during insulin combination therapy (Page 758, right col., line 3-15). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Ortega and Jarvinen and treat insulin deficiency disorder such as T2D with combination therapy of insulin and another agent such as S100A9 since Jarvinen teaches that glycemic control is better during insulin combination therapy (Page 758, right col., line 3-15). Examiner notes that the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). Obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties. See, e.g., In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988). (MPEP 2144.08 (II). The arguments are unpersuasive and the rejection is maintained.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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 Mercy H. Sabila whose telephone number is (571)272-2562. The examiner can normally be reached Monday - Friday 5:00 am - 3:00 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko G. Garyu can be reached at (571)270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MERCY H SABILA/Examiner, Art Unit 1654
/LIANKO G GARYU/Supervisory Patent Examiner, Art Unit 1654
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