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 .
Status of the Claims
Claims 62, 64, 69, 72-83, 88-93, and 95-99 are pending. Claims 62, 93, and 96 were amended in the response filed February 25, 2026.
Applicant’s election without traverse of glucagon SEQ ID NO: 37, insulin native with SEQ ID NOs: 124 and 125, and Fc in the reply filed on February 27, 2024, is acknowledged. The elected species read
on claims 62, 64, 69, 72-73, 88-93, and 95-99. Prior art is found on these species. The prior art search also yield an insulin species containing native insulin with A14 substituted with glutamic acid that reads on claims 74-75, 78, and 82-83. Therefore, the search is not extended in accordance with MPEP 803.02.
Claims 76-77 and 79-81 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claim Interpretation
The claim term “insulin” is defined on page 29 of the specification as “a kind of hormone secreted from beta cells of the pancreas, and generally has a role in regulating blood glucose in the body by promoting intracellular glucose uptake and inhibiting breakdown of fat.” The claim term “insulin” is further defined on page 30 of the specification as “native insulin” or “an analog, a derivative, or a fragment, which is obtained by alteration selected from the group consisting of substitution, addition, deletion, modification, and a combination thereof in one or more amino acids of the natural insulin” and as “not limited thereto.”
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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 62, 64, 69, 72-75, 78, 82-83, 88-93, and 95-99 are rejected under 35 U.S.C. 103 as being unpatentable over Jung et al. (US 2017/0196943 A1) in view of Pedersen et al. “Dual treatment with a fixed ratio of glucagon and insulin increases the therapeutic window of insulin in diabetic rats. Physiol Rep, 6 (6), 2018, e13657,” Green et al. (US 2006/0160722 A1), Song et al. (WO 2011/122921 A2) and Lee et al. (WO 2017/003191 A1).
The claims are drawn to a method for preventing or treating an insulin-related disease (Claim 62), a method for preventing or treating hypoglycemia (Claim 93), or a method for improving side effects of insulin (Claim 96), comprising administering a combination of two components: 1) insulin and 2) glucagon. The insulin and glucagon are each linked to an immunoglobulin Fc region to increase in vivo half-life thereof and function as a long-acting conjugate. The insulin and glucagon conjugates are administered at a weight ratio of 0.1:1 to 100:1. The elected insulin is native insulin with SEQ ID NOs: 124 and 125, and the elected glucagon is SEQ ID NO: 37.
Scope and Content of the Prior Art
Jung et al. disclose the same problem presented in the instant application: Jung et al. teach that there is an art-recognized need for “a therapeutic agent for diabetes which can reduce high blood glucose levels, suppress weight gain, and reduce the risk of hypoglycemia” (paragraph [0008]). Jung et al. teach a solution to this art-recognized problem: the combined administration of a long-acting insulin analog-immunoglobulin Fc conjugate and a long-acting GLP-1/glucagon dual agonist-immunoglobulin Fc conjugate (Example 11). Jung et al. present evidence that “the composition including both a long-acting insulin conjugate and a long-acting GLP-1/glucagon dual agonist conjugate has excellent ability to control blood glucose levels and has no side-effects of weight gain due to the administration of insulin exhibited superior therapeutic effect than the group in which conventional insulin and dual agonist drug were administered, respectively” (paragraph [0118]). Jung et al. teach that “the combined administration of insulin and GLP-1/glucagon dual agonist can prevent weight gain associated with a single administration of insulin, the risk of hypoglycemia can be reduced by reducing the amount of insulin, and further in order to exhibit more excellent effect of reduction of blood glucose levels than that of a single administration of the dual agonist, the combined administration of the two drugs can reduce side-effects and increase the effects as compared with the single administration of each drug” (paragraph [0037]). Jung et al. teach that “the composition for combined administration can be used as effective therapeutic agents while reducing side-effects of conventional therapeutic agent of diabetes” (paragraph [0037]).
Jung et al. teach that the long-acting insulin Fc conjugate contains the native insulin sequence with position 14 of the A chain substituted with Glu (Example 8). Therefore, the insulin is an insulin analog obtained by substitution of one amino acid of the natural insulin and falls within the definition of the claim term “insulin”. The conjugate contains the insulin covalently attached to the immunoglobulin Fc region (Example 8). The conjugate exhibits an increase in in vivo half-life (paragraph [0072]) and falls within the scope of Chemical Formula 1.
Jung et al. teach that the long-acting GLP-1/glucagon dual agonist-immunoglobulin Fc conjugate contains the GLP-1/glucagon dual agonist sequence: HAibQGTFTSDYSKYLDEKRAKEFVQWLMNTC (Example 10). The conjugate contains the glucagon covalently attached to the immunoglobulin Fc region (Example 10). The conjugate exhibits an increase in in vivo half-life (paragraph [0072]).
Differences between the prior art and the claims at issue
The prior art differs from the claims with respect to disclosure of the 1) elected species of insulin, 2) the claimed glucagon species, and 3) the claimed weight ratio of insulin : glucagon.
1) Elected species of insulin: Jung et al. teach that the long-acting insulin Fc conjugate contains the native insulin sequence with position 14 of the A chain substituted with Glu (Example 8), which falls within the scope of the claimed genus of insulin, but do not teach the elected species of insulin native with SEQ ID NOs: 124 and 125.
2) Claimed glucagon species: Jung et al. teach the long-acting GLP-1/glucagon dual agonist-immunoglobulin Fc conjugate contains the GLP-1/glucagon dual agonist sequence: HAibQGTFTSDYSKYLDEKRAKEFVQWLMNTC (Example 10), which is similar in sequence to the claimed glucagons, but do not teach the long-acting glucagon SEQ ID NOs: 20, 22, 33, 37, or 38 conjugated to Fc.
3) Claimed weight ratio of insulin : glucagon: Jung et al. teach that the “mole ratio of GLP-1/glucagon dual agonist : insulin may range from 1:0.05 to 1:50, but is not limited thereto as long as it shows the effect of the present invention” (paragraph [0016]). Jung et al. reduce to practice administration of a 1:1 molar ratio of GLP-1/glucagon dual agonist conjugate: insulin conjugate (Example 11). However, Jung et al. do not disclose the weight ratio of these components nor do they disclose the molecular weight (or molecular structure) of these components that would permit calculation of the weight ratio by one of ordinary skill in the art. Therefore, Jung et al. does not explicitly teach the limitation “wherein the insulin in the form of the long-acting conjugate and the glucagon in the form of the long-acting conjugate are administered at a weight ratio of 0.1:1 to 100:1”.
Resolving the level of ordinary skill in the pertinent art
1) Elected species of insulin: Song et al. teach an insulin conjugate comprising insulin linked to an immunoglobulin Fc region via a non-peptidyl polymer (p. 3, [21]). The conjugate has a longer half-life compared to unconjugated insulin and is a long-acting insulin formulation (p. 3, [14]; p. 9, [68]). The insulin may be native insulin with the A- and B-chains identical to elected species SEQ ID NOs: 124 and 125, respectively (p. 4, [26]-[30]). The long-acting conjugate containing the elected species native insulin is reduced to practice in Example 2. The long-acting insulin conjugate comprising insulin linked to an immunoglobulin Fc region is used to treat insulin-dependent diabetes (p. 10, [73]; p. 12, [96]).
2) Claimed glucagon species: Lee et al. teaches an glucagon conjugate comprising insulin linked to an immunoglobulin Fc region (p. 9, [151], [155]). The conjugate has a longer half-life compared to unconjugated glucagon and is a long-acting glucagon formulation (p. 9, [151]). Lee et al. teaches that the glucagon may be an analogue with sequence of General Formula I and may have a sequence of SEQ ID NOs: 2-44, which are identical to instant SEQ ID NOs: 2-44. The reference specifically discloses the elected species SEQ ID NO: 37 as well as each of the claimed species SEQ ID NOs: 20, 22, 33, and 38 (p. 8, [144]). The long-acting insulin conjugate comprising glucagon linked to an immunoglobulin Fc region is used to treat diabetes (p. 13, [215]). The species SEQ ID NO: 22 conjugated to an immunoglobulin Fc region was reduced to practice (Example 5, [587] and shown to reduce body weight (Experimental Example 2, [616]).
It is within the ordinary skill of the art to combine insulin and glucagon. Green et al. teach that pharmaceutical composition comprising both insulin and glucagon can be administered to control and treat diabetes while reducing or eliminating the risk of insulin-induced hypoglycemia (abstract). Pedersen et al. teach that dual treatment with a fixed ratio of glucagon and insulin increases the therapeutic window of insulin and protects against hypoglycemia caused by insulin (abstract).
3) Claimed weight ratio of insulin : glucagon: Jung et al. teach that the “mole ratio of GLP-1/glucagon dual agonist : insulin may range from 1:0.05 to 1:50, but is not limited thereto as long as it shows the effect of the present invention” (paragraph [0016]). It is unclear whether the range of molar ratios taught by Jung et al. corresponds to the claimed range of weight ratios. However, given the breadth of the prior art molar ratio range and the teaching that the ratio “is not limited thereto as long as it shows the effect of the present invention”, namely the ability to control blood glucose levels and reduce the risk of hypoglycemia in diabetes patients, it is likely that the prior art range of ratios touches, falls within, or overlaps with the claimed range.
It is within the ordinary skill of the art to optimize the insulin-glucagon ratio. The method of dose insulin-glucagon ratio optimization taught by Pedersen et al. comprises combining two fixed glucagon doses with increasing doses of insulin and measuring blood glucose responses and liver glycogen content in diabetic rates (page 3). The prior art of Green et al. teaches a method for determining the ratio of insulin and glucagon for co-administration that achieves management of blood glucose while reducing the risk of hypoglycemia (paragraph [0007]; Examples 1-2).
Considering objective evidence present in the application indicating obviousness or nonobviousness
The effect of the combination of glucagon and insulin on blood glucose (Example 10) and side effects (Example 11) presented in the instant specification are expected in view of the cited art which each disclose management of blood glucose while reducing the risk of hypoglycemia using a combination of insulin and glucagon.
Rationale for Obviousness
1) Elected species of insulin: It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the long-acting insulin of Song et al. for the long-acting insulin in the combination with long-acting GLP-1/glucagon dual agonist taught by Jung et al. The rationale for obviousness is simple substitution of one known element for another to obtain predictable results (MPEP § 2143.01(B)). Song et al. teach an insulin conjugate comprising insulin linked to an immunoglobulin Fc region via a non-peptidyl polymer (p. 3, [21]). The insulin is native insulin with the A- and B-chains identical to elected species SEQ ID NOs: 124 and 125, respectively (p. 4, [26]-[30]; reduced to practice in Example 2), which is the substituted component. The function of native insulin conjugated to an immunoglobulin Fc region is known in the art because Song et al. teach that it is used to treat insulin-dependent diabetes (p. 10, [73]; p. 12, [96]) and is a long-acting formulation with a longer half-life compared to unconjugated insulin (p. 3, [14]; p. 9, [68]). Therefore, the substituted components and their functions were known in the art. One of ordinary skill in the art would expect that the Fc immunoglobulin-native insulin conjugate performs the function of treating diabetes as a long-acting insulin the combination in view of the teaching of Song et al. Therefore, one of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have been predictable. The rationale to support a conclusion that the claim would have been obvious is that the substitution of one known element for another yields predictable results to one of ordinary skill in the art.
2) Claimed glucagon species: It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the long-acting glucagon of Lee et al. for the long-acting GLP-1/glucagon dual agonist in the combination with long-acting insulin taught by Jung et al. The rationale for obviousness is some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention (MPEP § 2143.01(G)). In the instant case, Lee et al. teaches that oxyntomodulins (aka GLP-1/glucagon dual agonists) have the disadvantage of a fixed activity ratio between the GLP-1 and glucagon activities ([14]). In addition, Lee et al. teach that as an alternative to oxyntomodulins, glucagon derivatives that have the advantage of having improved therapeutic effects of glucagon on hypoglycemia and obesity, and improved physical properties, solubility, and stability ([16]). One of ordinary skill in the art would have been motivated to substitute the glucagons of Lee et al. for the oxyntomodulins of Jung et al. to take advantage of these properties. Therefore, there was some teaching, suggestion, or motivation, either in the references themselves or in the knowledge generally available to one of ordinary skill in the art, to modify the reference or to combine reference teachings. One of ordinary skill in the art would predict that glucagon and insulin can be combined because both Green et al. and Pedersen et al. teach that this combination can be used to treat diabetes and control hypoglycemia from insulin. Therefore, there was a reasonable expectation of success. The rationale to support a conclusion that the claim would have been obvious is that "a person of ordinary skill in the art would have been motivated to combine the prior art to achieve the claimed invention and whether there would have been a reasonable expectation of success in doing so." DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1360, 80 USPQ2d 1641, 1645 (Fed. Cir. 2006).
3) Claimed weight ratio of insulin : glucagon: MPEP § 2144.05(II)(A) states: Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)
In the instant case, Jung et al. teach that the “mole ratio of GLP-1/glucagon dual agonist : insulin may range from 1:0.05 to 1:50, but is not limited thereto as long as it shows the effect of the present invention” (paragraph [0016]). It is unclear whether the range of molar ratios taught by Jung et al. corresponds to the claimed range of weight ratios. However, given the breadth of the prior art molar ratio range and the teaching that the ratio “is not limited thereto as long as it shows the effect of the present invention”, namely the ability to control blood glucose levels and reduce the risk of hypoglycemia in diabetes patients, it is likely that the prior art range of ratios touches, falls within, or overlaps with the claimed range.
It would have been routine optimization to arrive at the claimed invention. The prior art of Pedersen et al. teaches a method for determining the ratio of insulin and glucagon for co-administration that achieves management of blood glucose while reducing the risk of hypoglycemia. The method of dose insulin-glucagon ratio optimization taught by Pedersen et al. comprises combining two fixed glucagon doses with increasing doses of insulin and measuring blood glucose responses and liver glycogen content in diabetic rates (page 3).
The prior art of Green et al. teaches a method for determining the ratio of insulin and glucagon for co-administration that achieves management of blood glucose while reducing the risk of hypoglycemia (paragraph [0007]; Examples 1-2).
A person of ordinary skill in the art would have had a reasonable expectation of success to formulate the claimed range of insulin-glucagon weight ratios given that the objective of the prior art of Jung et al., Pederson et al., and Green et al. is the same as the objective of the instant invention: management of blood glucose while reducing the risk of hypoglycemia using a combination of insulin and a second agent. Furthermore, Pederson et al. and Green et al. evidence that the combination of insulin and glucagon to manage blood glucose while reducing the risk of hypoglycemia is broadly known in the prior art.
Therefore, claims 62, 93, and 96 are obvious over Jung et al., Pedersen et al., Green et al., Song et al. and Lee et al.
With respect to claims 64, and 98-99, Jung et al., Pedersen et al., and Green et al. each teach a method of treating diabetes while reducing the risk of hypoglycemia and/or suppressing weight gain.
With respect to claim 69, positions 16 and 20 in SEQ ID NOs: 20, 22, 37, and 38, which are taught by Lee et al., form a ring (Table 1).
With respect to claim 72, Lee et al. teach SEQ ID NO: 37 (Table 1).
With respect to claims 73-74, Jung et al. teach that the insulin is an insulin analog obtained by substitution of one amino acid of the natural insulin, specifically the native insulin sequence with position 14 of the A chain substituted with Glu (Example 8).
With respect to claims 75, 78, and 82-83, Jung et al. teach the long-acting insulin conjugate contains the native insulin sequence with position 14 of the A chain substituted with Glu (Example 8). The resulting sequence would be (paragraph [0019]):
A chain: Gly-Ile-Val-Glu-Gln-Cys-Cys-Thr-Ser-Ile-Cys-Ser- Leu-Glu-Gln-Leu-Glu-Asn-Tyr-Cys-Asn
B chain: Phe-Val-Asn-Gln-His-Leu-Cys-Gly-Ser-His-Leu-Val- Glu-Ala-Leu-Tyr-Leu-Val-Cys-Gly-Glu-Arg-Gly-Phe- Phe-Tyr-Thr-Pro-Lys-Thr
which reads on General Formula 3 and General Formula 4 and which include cysteines capable of forming disulfides between the A and B chains.
With respect to claim 88, Jung et al. teach that the immunoglobulin Fc region may be aglycosylated (paragraph [0067]), may contain a part or all of the heavy-chain constant region 2 (CH2), the heavy-chain constant region 3 (CH3), the heavy-chain constant region 1 (CH1) and the light-chain constant region 1 (CL1) of the immunoglobulin (paragraph [0055]-[0056]), may be one in which a region capable of forming a disulfide bond is deleted, certain amino acid residues are eliminated at the N-terminal end of a native Fc form, a methionine residue is added thereto, effector functions are removed, or a deletion may occur in a complement-binding site, such as a C1q-binding site and an ADCC (paragraph [0057]), or may be derived from IgG, IgA, IgD, IgE and IgM (paragraph [0063]).
With respect to claims 89-91, Jung et al. teach that the linker between the glucagon/insulin and the Fc region may be a non-peptidyl polymer, especially polyethylene glycol (paragraphs [0050]-[0052]).
With respect to claims 92, 95, and 97, Jung et al. teach that the long-acting insulin conjugate and the long-acting GLP-1/glucagon dual agonist conjugate may be simultaneously, sequentially, or reversely administered (paragraph [0073]).
Response to Arguments
Applicant's arguments filed February 25, 2026, have been fully considered but they are not persuasive.
First, Applicant traverses the rejection on the grounds that Jung discloses a long-acting oxyntomodulin (GLP-1/glucagon dual agonist) and does not teach or suggest substituting the dual agonist oxyntomodulin with the single agonist glucagon. This argument is not persuasive because the prior art of Lee et al. teaches that glucagon is an alternative to oxyntomodulin that addresses the disadvantage of oxyntomodulins (aka GLP-1/glucagon dual agonists) having fixed activity ratio between the GLP-1 and glucagon activities ([14]). In response, Applicant further argues that based on Lee, if the substitution were considered, oxyntomodulin would be replaced with a combination or GLP-1 and glucagon, rather than glucagon alone.
This argument is not persuasive because the purpose of Jung et al. is to treat diabetes by reducing high blood glucose levels while suppressing weight gain, and reducing the risk of hypoglycemia (paragraph [0008]). Lee et al. specifically addresses properties and functions of the glucagons that are relevant to the objective of Jung et al. First, Lee et al. teach that the glucagons are long-acting and that this properties is achieved by the same means utilized in Jung et al., conjugation to immunoglobulin Fc (p. 13, [215]). Second, Lee et al. teach that the glucagon derivatives (e.g. SEQ ID NO: 20) have improved therapeutic effects on hypoglycemia and obesity ([16]; Experimental Example 2, [616]): “As a result of the measurements of changes in body weight, as can be confirmed in FIG. 4, each of the groups administered with the long-acting derivative of SEQ ID NO: 20 (8.8 nmol/kg, injection once every 2 days) alone showed a decrease in body weight by -25% and -29%, respectively, compared to that before administration.” Given the general discussion in Lee et al. and the evidence provided in Experimental Example 2, POSITA would predict that the glucagons of Lee et al. would function in the method of Jung et al., the purpose of which is to treat diabetes while managing hypoglycemia and obesity from insulin. Although the addition of GLP-1 to the glucagon could result in even more effects, this does not change the fact that Lee et al. teach that glucagon alone can work.
This argument is also not persuasive because the claim does not preclude the inclusion of an additional agent such as a GLP-1. The transitional phrase “comprising” allows additional unrecited elements.
Next, Applicant traverses the rejection on the grounds that POSITA would not combine Pedersen and Green, which disclose combining insulin and glucagon, with Jung, which discloses combining insulin with a GLP-1/glucagon dual agonist. This argument is not persuasive. The motivation to combine Lee et al. with Jung et al. comes from the suggestion that the glucagons in Lee et al. are an alternative to oxyntomodulins such as those taught by Jung et al. POSITA would further recognize that combining glucagons and insulin is a valid approach given the teachings of Pedersen et al. and Green et al.
Next, Applicant traverses the rejection on the grounds that Pedersen and Green fail to teach insulin and glucagon in conjugate form. This argument is not persuasive because the advantages of conjugation are taught by Jung et al., Lee et al. and Sung et al.
The rejection is maintained for the reasons presented above.
Conclusion
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.
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/CHRISTINA BRADLEY/Primary Examiner, Art Unit 1654