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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-15, in the reply filed on 2/12/2026 is acknowledged. Claims 16-19 and 20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 2/12/2026.
Claim 1 is directed to an allowable product. Pursuant to the procedures set forth in MPEP § 821.04(B), claims 16-20, directed to the process of making or using an allowable product, previously withdrawn from consideration as a result of a restriction requirement, claims 16-20 are hereby rejoined and fully examined for patentability under 37 CFR 1.104.
Because all claims previously withdrawn from consideration under 37 CFR 1.142 have been rejoined, the restriction requirement as set forth in the Office action mailed on 12/5/2025 is hereby withdrawn. In view of the withdrawal of the restriction requirement as to the rejoined inventions, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Priority
Priority to US 63/104,196, filed 10/22/2020, is acknowledged.
Claim Status
Claims 1-4, 7-8, 10, and 16-23, filed 7/22/2026, are pending. Claims 1-4, 7-8, 10, and 16-23 are under examination. Claims 5-6, 9, and 11-15 are canceled.
Previous Claim Objections
Claim 3 was previously objected to because of the following informalities. Claim 3 uses the term “comprised”. For consistency, using the term “comprises” would be better. “Comprised” is past tense, and the rest of the verbs in the claim are in the present tense. Appropriate correction is required.
Response to Arguments
Applicant’s arguments, see Applicant Reply page 6, para. 2, filed 7/22/2026, with respect to claim 3 have been fully considered and are persuasive. The objection to claim 3 has been withdrawn.
New Claim Objections
Claims 1-4, 7-8, 10, and 16-23 are objected to because of the following informalities. The claims use a mixture of lower case and capitalized term “claim”. For consistency, please choose one convention for uniformity. Appropriate correction is required.
Claim 16 is objected to because of the following informalities. The term “glycine” is inappropriately capitalized in line 5. Appropriate correction is required.
Claim 16 is objected to because of the following informalities. The term “amino acid” in line 5 is not normally hyphenated. Appropriate correction is required.
Previous Claim Rejections - 35 USC § 112
Claims 1-15 were previously 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.
Response to Arguments
Applicant’s arguments, see Applicant Reply page 6, para. 3, filed 7/22/2026, with respect to claims 1-15 have been fully considered and are persuasive. The rejection of claims 1-4, 7-8, and 10 has been withdrawn. Claims 5-6, 9, and 11-15 have been canceled, rendering those rejections moot.
Previous Claim Rejections - 35 USC § 103
Claims 1-4, 6, 7, and 10 were previously rejected under 35 U.S.C. 103 .
Response to Arguments
Applicant’s arguments, see Applicant Reply page 6, para. 6, filed 7/22/2026, with respect to claims 1-15 have been fully considered and are persuasive. The rejection of claims 1-4, 6-7, and 10 has been withdrawn. Claims 5-6, 9, and 11-15 have been canceled, rendering those rejections moot.
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.
Claims 16-20 are 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.
Regarding claim 16, claim 16 refers to claims 1-15, which was originally a proper multiple dependent form, but now claims 5-6, 9, and 11-15 have been canceled, which makes reference to said claims result in an indefinite claim scope.
Claim 16 uses the phrase "i.e." which renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Also, claim 16 refers to “…an analog of any one of…”. It is not clear as to which analog exactly is being referred to. Furthermore, claim 1 references an insulin analog, not just an analog. There is insufficient antecedent basis for this limitation in the claim. Examiner suspects “the insulin analog of any one of…” was intended here.
Furthermore, claim 16 refers to the A-chain modification of a glucose binding element as optional, but this feature is not optional in claim 1. It is not clear whether this feature is required or not by claim 16. Clarification is required.
Claim 16 recites “…which upon modification contains no tryptic cleavage site…”. It is not clear whether this conditional statement applies to the B-chain, the synthetic peptide or the analog overall. Clarification is required.
Consequently, claim 16 is rejected.
Regarding claim 17, claim 16 is rejected as described above. Claim 17 does not resolve the indefiniteness of claim 16. Additionally, claim 17 also uses “…an insulin analog…”. It is not clear as to which analog exactly is being referred to.
Consequently, claim 17 is rejected.
Regarding claim 18, claim 16 is rejected as described above. The phrase "such as" in line 2 renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Also, claim 18 refers to “A method of claim 16…”. It is not clear as to which method exactly is being referred to. Examiner suspects “The method of claim 16…” was intended here.
Claim 18 fails to resolve the indefiniteness of claim 16.
Consequently, claim 18 is rejected.
Regarding claim 19, the phrase "such as" in line 2 renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Also, claim 19 fails to resolve the indefiniteness of claim 16.
Consequently, claim 19 is rejected.
Regarding claim 20, claim 20 refers to “…an insulin analog of any one of…”. It is not clear as to which analog exactly is being referred to. Examiner suspects “…the insulin analog of any one of…” was intended here.
Claim 20 also refers to claims 1-15, which was originally a proper multiple dependent form, but now claims 5-6, 9, and 11-15 have been canceled, which makes reference to said claims result in an indefinite claim scope.
Consequently, claim 20 is rejected.
Claims 18-19 are 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 insulin, insulin analogues, proinsulin, or mini-insulin, does not reasonably provide enablement for any possible polypeptide. 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.
In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is "reasonable" or is "undue." Consistent with Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Wands factors continue to provide a framework for assessing enablement in a utility application or patent, regardless of technology area. Guidelines for Assessing Enablement in Utility Applications and Patents in View of the Supreme Court Decision in Amgen Inc. et al. v. Sanofi et al., 89 FR 1563 (January 10, 2024). These factors include, but are not limited to:
The breadth of the claims;
Claims 18 and 19 encompass the digestion of any possible single-chain polypeptide to produce the des-octapeptide[B23-B30].
The nature of the invention;
The invention is a method for preparing an insulin analog by means of trypsin-mediated semi-synthesis. The particular step in question the starting polypeptide recited by claims 18 and 19.
The state of the prior art;
The activity of polypeptides is tremendously influenced by their sequence. For example, a single point mutation can change the biophysical properties of a peptide: “In summary, we have shown that the structural changes in the fibrillar state of the Aβ42 peptide that are observed to occur upon introduction of single point mutations can be accompanied by changes in the dominance of the microscopic processes by which these aggregates are themselves formed.” (Bolognesi et al. ACS Chem Bio 9:2 (2013) page 381 col. 2 para. 3) and “In summary, while ovispirin-1 and novispirin G-10 both had solution structures that were helical and amphipathic in the presence of TFE, a relatively simple change in their primary structure (a single glycine–isoleucine exchange) had profound effects on their respective toxicities for human erythrocytes and epithelial cells.” (Sawai et al. Protein Eng. 15:3 (2002) page 232 col. 1 para. 3).
Furthermore, many sequences allowed by the current scope of the claims, result in non-functional aggregates. Wang (Wang, et al. MAbs. Vol. 1. No. 3. Taylor & Francis, (2009)) discloses a variety of aggregation prone motifs that occur in commercial antibodies (Wang, page 262, Table 2). The scope of the claims currently may incorporate such motifs and result in non-functional aggregates.
Finally, Zhou et al. (Zhou, et al. Biochimica et Biophysica Acta (BBA)-Biomembranes 1858.8: 1914-1925 (2016)) discloses that peptides are also subject to significant activity changes from a single mutation: “In our study, we constructed two anticancer peptides with only one difference in residue, but they showed dissimilar modes of action. One could penetrate into cells, target on mitochondria, and induce cell apoptosis, while the other could cause cell membrane lysis. This finding provides us a good example to study the structure-function relationship of ACPs as important drugs.” (Zhou et al., Abstract).
(D) The level of one of ordinary skill;
A person of ordinary skill in the art in the field of fusion proteins is usually at least a Master’s level education.
(E) The level of predictability in the art;
As described above, the predictability of this art is very poor.
(F) The amount of direction provided by the inventor and the existence of working examples and the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Applicant provides efficacy data for the case of a previously folded A-chain of insulin.
Regarding claim 18, claim 18 recites further limitations to the method of claim 16. However, claim 18 makes reference to the case wherein the starting polypeptide may be any possible polypeptide. Because of the impact of polypeptide sequence on function, most polypeptides would not be suitable for this purpose as they would lack insulin activity. Applicant provides the example of an A-chain starting material in the specification, and a person of ordinary skill in the art would reasonably conclude that other insulin analogs are viable starting materials, just not the entire breadth of all polypeptides.
It would require undue experimentation to test all possible polypeptides for suitability as starting materials. 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.
Consequently, claim 18 is rejected.
Regarding claim 19, claim 19 recites further limitations to the method of claim 16. However, claim 19 makes reference to the case wherein the starting polypeptide may be any possible polypeptide. Because of the impact of polypeptide sequence on function, most polypeptides would not be suitable for this purpose as they would lack insulin activity. Applicant provides the example of an A-chain starting material in the specification, and a person of ordinary skill in the art would reasonably conclude that other insulin analogs are viable starting materials, just not the entire breadth of all polypeptides.
It would require undue experimentation to test all possible polypeptides for suitability as starting materials. 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.
Consequently, claim 19 is rejected.
Claims 20 is 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 alleviating symptoms in a diabetic patient, does not reasonably provide enablement for treating a diabetic patient, because treating has been redefined to include prevention and curing the disease state:
“As used herein, the terms "treat" or "treatment" encompass both "preventative" and "curative" treatment. "Preventative" treatment is meant to indicate a postponement of development of a disease, a symptom of a disease, or medical condition, suppressing symptoms that may appear, or reducing the risk of developing or recurrence of a disease or symptom.
"Curative" treatment includes reducing the severity of or suppressing the worsening of an existing disease, symptom, or condition. Thus, treatment includes ameliorating or preventing the worsening of existing disease symptoms, preventing additional symptoms from occurring, ameliorating or preventing the underlying systemic causes of symptoms, inhibiting the disorder or disease, e.g., arresting the development of the disorder or disease, relieving the disorder or disease, causing regression of the disorder or disease, relieving a condition caused by the disease or disorder, or stopping the symptoms of the disease or disorder.” (Specification, para. [0303]).
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.
In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is "reasonable" or is "undue." Consistent with Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Wands factors continue to provide a framework for assessing enablement in a utility application or patent, regardless of technology area. Guidelines for Assessing Enablement in Utility Applications and Patents in View of the Supreme Court Decision in Amgen Inc. et al. v. Sanofi et al., 89 FR 1563 (January 10, 2024). These factors include, but are not limited to:
The breadth of the claims;
Claim 20, as described above, encompasses curing and preventing diabetes in a diabetic patient.
The nature of the invention;
The invention is a method for treating a diabetic patient with a physiologically effective amount of an insulin analogue.
The state of the prior art;
Roglic et al. (Roglic, et al. International Journal of Noncommunicable Diseases 1.1: 3-8. (2016)) summarizes the types and causes of diabetes:
“Diabetes is a chronic illness characterized by elevated levels of blood glucose, accompanied by disturbed metabolism of fats and proteins. Blood glucose rises because it cannot be metabolized in the cells, due to lack of insulin production by the pancreas or the inability of the cells to effectively use the insulin that is being produced. There are three major types of diabetes: (1) Type 1, in which the pancreas does not produce insulin; (b) type 2 in which the body cells are resistant to the action of insulin that is being produced and over time the production of insulin progressively decreases; and (c) gestational diabetes which occurs in pregnancy and can cause some complications during the pregnancy, and at birth and increases the risk of type 2 diabetes in the mother and obesity in the offspring.
In addition, there are two other categories of glucose intolerance - impaired fasting glucose (IFG) and impaired fasting glycemia (IGT) that are intermediate conditions between normal and diabetic blood glucose levels, although the transition is not inevitable. People with IFG and IGT are at increased risk of CVD than people with normal blood glucose values.” (Roglic et al., Abstract).
(D) The level of one of ordinary skill;
A person of ordinary skill in the art in the field of fusion proteins is usually at least a Master’s level education.
(E) The level of predictability in the art;
The causes of diabetes are fairly well-understood as described above. The activity of polypeptides inside a human body is far more unpredictable.
(F) The amount of direction provided by the inventor and the existence of working examples and the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Applicant provides efficacy data in the form of PCR assays that show changes in gene regulation in HepG2 cells.
Regarding claim 20, claim 20 encompasses the concept of preventing and/or curing diabetes by way of the redefined term “treating”. As described above by Roglic, prevention of type 1 diabetes would require extensive gene editing, as would the curing of type 1 diabetes.
Applicant only shows some gene regulation modification in HepG2 cells, which provides support for the alleviation of symptoms, but does not enable preventing or curing any possible diabetic disease.
It would require undue experimentation to test the claimed method for its ability to cure or prevent any possible diabetes disease state. 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.
Consequently, claim 20 is rejected.
Free of the Prior Art
Claim 9 was previously free of the prior art. While L-DOPA at position B26 is not specifically disclosed, Žáková et al. (Žáková, et al. Biological Crystallography 70.10: 2765-2774 (2014)) discloses that PheB6 results in an inactive form of insulin (Žáková, et al., page 2769, Table 2). Phenylalanine is a very close structural analog to L-DOPA and consequently, a person of ordinary skill in the art would be motivated to not make such a substitution based off the results of Žáková. Therefore, the insulin analog of previous claim 9 was novel and nonobvious.
Previous claim 9 has been canceled and incorporated into amended claim 1. Consequently, all current claims are novel and nonobvious, including the new claims 21-23.
Allowable Subject Matter
Claims 1-4, 7-8, 10, and 21-23 are allowable.
Claims 1-4, 7-8, 10, and 21-23 are free of the prior art and no further rejections are made against these claims.
Conclusion
Claims 1-4, 7-8, 10, and 21-23 are allowable.
Claims 16-20 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to David Paul Bowles whose telephone number is (571)272-0919. The examiner can normally be reached Monday-Friday 8:30-5:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko Garyu can be reached on (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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/DAVID PAUL BOWLES/ Examiner, Art Unit 1654
/LIANKO G GARYU/ Supervisory Patent Examiner, Art Unit 1654
