DETAILED ACTION
The present application is being examined under the pre-AIA first to invent provisions.
Applicant’s response and amendments received April 17, 2026 are acknowledged.
Claims 1, 18, and 19 have bene amended.
Claims 1-19 are pending in the instant application.
Applicant’s election of the diabetes autoantigen species of “preproinsulin” in the reply filed on September 26, 2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 1-19 are under examination in this office action.
Claim Rejections - 35 USC § 112
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.
Claim 18 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
In claim 18, applicant has recited that the administration methods of claim 1 are capable of “preventing the onset of diabetes”. Such an administration is highly problematic. First, while is possible to experimentally induce diabetes in animal models (such as NOD mice) such that artisans know who will and who will not develop diabetes, humans are not amenable to such foreknowledge with patients being diagnosed as having diabetes only once clinical signs and symptoms of the disease are manifest. Obviously if the patient is already showing signs of the disease it can no longer be “prevented” and the instant application does not appear to provide any new diagnostic assay to determine who will or will not develop diabetes in in the future. Further, in working example 4 which did use a mouse model of diabetes the administration of abatacept in combination with a B-chain vaccine was unable to prevent disease, even though it did slow the progress of disease as compared to controls. Thus, while the instant claimed methods might be able to inhibit the onset of diabetes as compared to doing nothing, it does not appear reasonable that the instant claimed methods are capable of the full breadth of “preventing” disease as presently recited.
Applicant's arguments filed April 17, 2026 have been fully considered but they are not persuasive. Applicant argues “Applicants have amended Claims 18 (and 19) to address the Examiner's concerns about the claimed methods preventing the onset of diabetes. Accordingly, this rejection is deemed to have been avoided by amendment.”
This argument is not persuasive. Applicant amended claim 18 to recite “preventing the onset of insulin dependent diabetes” rather than “preventing the onset of diabetes” as previously presented. Such an amendment in no way removes issues concerning “prevention” particularly in human subjects who are only identified after developing clinical signs and symptoms of disease, and in terms of efficacy even in a mouse model as discussed in the rejection of record. The rejection is 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.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of pre-AIA 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a) the invention was known or used by others in this country, or patented or described in a printed publication in this or a foreign country, before the invention thereof by the applicant for a patent.
(b) the invention was patented or described in a printed publication in this or a foreign country or in public use or on sale in this country, more than one year prior to the date of application for patent in the United States.
(e) the invention was described in (1) an application for patent, published under section 122(b), by another filed in the United States before the invention by the applicant for patent or (2) a patent granted on an application for patent by another filed in the United States before the invention by the applicant for patent, except that an international application filed under the treaty defined in section 351(a) shall have the effects for purposes of this subsection of an application filed in the United States only if the international application designated the United States and was published under Article 21(2) of such treaty in the English language.
The rejection of claims 1 and 3-7 under pre-AIA 35 U.S.C. 102(a) as being anticipated by Marketwired as evidenced by Chatenoud et al. has been withdrawn in view of applicant’s amendment to claim 1 received April 17, 2026 which adds additional limitations not disclosed in the press release.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
Claims 1-15 and 17-19 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Cohen et al. (US Patent 8,497,247) in view of US 2003/0045467.
Cohen et al. disclose the administration of CTLA4-Ig for the treatment of diabetes mellitus (see entire document, particularly the abstract and claims). The amount of CTLA4-Ig which is to be administered is disclosed in both an individualized basis in mg/kg as well as incremental dosing such as 500 mg for a subject weighing less than 60 kg, 750 mg for a subject weighing 60-100 kg, and 1000 mg for subjects over 100kg (see particularly columns 19 and 20 and columns 31-33) and note that such doses anticipate that presently recited in instant claim 30. Such administrations are disclosed as occurring via numerous routes including intravenous, intramuscular, and subcutaneously either alone or in combination with additional therapeutic agents (see particularly column 39). The use of carriers in pharmaceutical compositions, including oil-based, are disclosed by Cohen et al. (see particularly column 34). It should be noted that the '247 patent to Cohen et al. claims continuity to applications disclosed by paragraph [0029] of the instant specification as disclosing abatacept and thus based upon the evidence presently of record the CTLA4-Ig of Cohen et al. is abatacept. Notably, applicant did not traverse such a finding in great grandparent application 14/253,432 or any subsequent child application. Administration of CTLA4-Ig in combination with additional therapeutic agents is disclosed (see column 40 for example) but these teachings differ from the instant claimed invention in that administration of a diabetes autoantigen, such as preproinsulin, in combination with CTLA4-Ig is not disclosed.
The ‘467 document discloses pharmaceutical compositions which contain preproinsulin in combination with an oil-based adjuvant for the treatment of diabetes, with IFA and Montanide ISA beings specifically taught as oil-based adjuvants (see entire document, particularly paragraphs [0005], [0006], [0009], [0026], [0039-0041], [0117], and claims 1-30, most particularly claims 2, 3, and 9). It should be noted that Montanide ISA contains mannide oleate (see for example paragraphs [0113] and [0163]). The ratio of autoantigen to adjuvant in such composition are disclosed as being 50/50 by weight (see for example paragraphs [0069] and [0089]). Such compositions are disclosed as being administered via multiple routes including parenterally, subcutaneously, intramuscularly, and mucosally (see for example paragraphs [0184-0185]). Additionally, fragments of insulin comprising residues 33-47 or SEQ ID NO:1 are explicitly disclosed as preferred embodiments for autoantigens present in such pharmaceutical compositions (see most particularly paragraph [0027]).
Therefore, it would have been obvious to a person of ordinary skill in the art at the time the invention was filed to combine CTLA4-Ig in a composition with the diabetes autoantigen preproinsulin, based on the teachings of Cohen that CTLA4-Ig can be used to treat diabetes and combined with other agents known to treat the autoimmune disease, and the teachings of the ‘467 document that preproinsulin is to be administered in conjunction with oil based adjuvants including IFA for the treatment of diabetes. Applicant is reminded that "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose .... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). See MPEP 2144.06.
It is noted that ‘467 document does not appear to disclose specific doses for preproinsulin which are administered to treat diabetes. However, optimizing the dose of a therapeutic agent to best treat a disease is a routine and common practice for artisans as is acknowledged by the ‘467 document (see particularly paragraph [0186]) and thus determining how much autoantigen to combine with the CTLA4-Ig of Cohen et al. is a matter of optimizing a results effective variable, with the “variable” being the dose and the “result” being patient treatment/outcome. It should be pointed out that the courts have long ruled that “[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). Given that the amount of drug in a dose is correlated with efficacy of disease treatment as discussed above, finding a suitable dose for administration is prima facie obvious in the absence of evidence to the contrary.
Applicant's arguments filed April 17, 2026 have been fully considered but they are not persuasive. Applicant argues the rejection is not sustainable as CTLA4 fusion proteins are “primarily intended to suppress immune responses” while antigen specific therapies require induction of immune responses and thus artisans would not combine such reagents as part of a therapeutic intervention.
This argument is unpersuasive as the “counterintuitive” combination of CTLA4 fusion proteins and an autoimmune antigen was known in the prior art to be therapeutically effective as is most readily evidenced by the Marketwired press release (of record) as well as Gray et al. (US 2004/0151725, of record, see entire document most particularly paragraph [0095]). Further, as set forth in the rejection of record, Cohen et al. disclosing their CTLA4 administrations with other modalities to treat diabetes, and antigen in adjuvant strategies for autoimmune disease treatment, including diabetes, was well known in the art as discussed in the ‘467 document. Thus, contrary to applicant’s arguments, artisans would not have been dissuaded from arriving at the inventions as presently claimed and would have a more than reasonable expectation of success in doing so. The rejection is maintained.
Claims 1-15 and 17-19 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Marketwired in view of Cohen et al. (US Patent 8,497,247) and in view of US 2003/0045467.
Marketwired discloses that administration of abatacept, a CTLA4-Ig fusion protein, in combination with diabetes autoantigens, provided evidence of clinical efficacy by strengthening immune regulation in a disease-specific manner (see entire document, most particularly the fourth paragraph). These teachings differ from the instant claimed invention in that the diabetes autoantigen is insulin B chain rather than preproinsulin and specific masses for active ingredients and adjuvants are not disclosed.
Cohen et al. disclose the administration of CTLA4-Ig for the treatment of diabetes mellitus (see entire document, particularly the abstract and claims). The amount of CTLA4-Ig which is to be administered is disclosed in both an individualized basis in mg/kg as well as incremental dosing such as 500 mg for a subject weighing less than 60 kg, 750 mg for a subject weighing 60-100 kg, and 1000 mg for subjects over 100kg (see particularly columns 19 and 20 and columns 31-33) and note that such doses anticipate that presently recited in instant claim 30. Such administrations are disclosed as occurring via numerous routes including intravenous, intramuscular, and subcutaneously either alone or in combination with additional therapeutic agents (see particularly column 39). The use of carriers in pharmaceutical compositions, including oil-based, are disclosed by Cohen et al. (see particularly column 34). Administration of CTLA4-Ig in combination with additional therapeutic agents is also disclosed (see column 40 for example) and based upon the evidence of record the CTLA4-Ig fusion protein used by Cohen et al. appears to be abatacept.
The ‘467 document discloses pharmaceutical compositions which contain preproinsulin in combination with an oil-based adjuvant for the treatment of diabetes, with IFA and Montanide ISA beings specifically taught as oil-based adjuvants (see entire document, particularly paragraphs [0005], [0006], [0009], [0026], [0039-0041], [0117], and claims 1-30, most particularly claims 2, 3, and 9). It should be noted that Montanide ISA contains mannide oleate (see for example paragraphs [0113] and [0163]). The ratio of autoantigen to adjuvant in such composition are disclosed as being 50/50 by weight (see for example paragraphs [0069] and [0089]). Such compositions are disclosed as being administered via multiple routes including parenterally, subcutaneously, intramuscularly, and mucosally (see for example paragraphs [0184-0185]). Additionally, fragments of insulin comprising residues 33-47 or SEQ ID NO:1 are explicitly disclosed as preferred embodiments for autoantigens present in such pharmaceutical compositions, and it should be readily apparent that any insulin is a fragment of the preproinsulin precursor polypeptide (see most particularly paragraph [0027]).
Therefore, it would have been obvious to a person of ordinary skill in the art at the time the invention was filed to modify the teachings of the Marketwired reference to arrive at the claimed invention. Specifically, artisans would know that abatacept successfully treats autoimmune diabetes as evidenced by both the Marketwired document and Cohen et al., with increased efficacy being expected by combining abatacept with diabetes autoantigens as is taught by the Marketwired reference. Thus it would have been obvious to an ordinary artisan that full length preproinsulin could be substituted for the insulin B-chain used in the as they are related (specifically B chain is a fragment of preproinsulin) and both are taught for use in vaccines to treat diabetes. Applicant is reminded that "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose .... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). See MPEP 2144.06.
It is noted that ‘467 document does not appear to disclose specific doses for preproinsulin which are administered to treat diabetes. However, optimizing the dose of a therapeutic agent to best treat a disease is a routine and common practice for artisans as is acknowledged by the ‘467 document (see particularly paragraph [0186]) and thus determining how much autoantigen to combine with abatacept is a matter of optimizing a results effective variable, with the “variable” being the dose and the “result” being patient treatment/outcome. It should be pointed out that the courts have long ruled that “[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). Given that the amount of drug in a dose is correlated with efficacy of disease treatment as discussed above, finding a suitable dose for administration is prima facie obvious in the absence of evidence to the contrary.
Applicant's arguments filed April 17, 2026 have been fully considered but they are not persuasive. Applicant argues that it is hard to mix fusion proteins and adjuvants in a vaccine, and that identifying appropriate dosing is non-trivial.
These arguments have been considered and are not persuasive. It should be note that applicant has claimed that the fusion protein and diabetes autoantigen are to be administered separately (claim 17) and in the same composition (claim 10), and that the broadest claims recite no dosing information whatsoever. Thus if applicant’s arguments were persuasive the lack of such limitations in all claims would seemingly be evidence that the full scope of what has bene claimed is not reasonably enabled. However, such arguments are not persuasive and as such no new rejections under 35 USC 112 pointing to applicant’s response as evidence have been set forth. As discussed in the rejection of record, the Marketwired document teaches administration of soluble CTLA4 and peptide vaccine in combination, while both Cohen et al. and the ‘467 publication indicate that their compositions are suitable for combining with additional treatment modalities. The rejection of record is maintained.
Claims 1-15 and 17-19 are rejected under pre-AIA 35 U.S.C. 103(a) as being obvious over Chatenoud et al. in view of US 2003/0045467.
Chatenoud et al. disclose that Abatacept (CTLA4-Ig), insulin and its fragments, GAD 65 and a fragment of HSP60 all have been used in clinical trials for the treatment of diabetes mellitus (see entire document, particularly the abstract and pages 6 and 12-13). Administration of CTLA4-Ig is disclosed as They disclose that the best way to treat diabetes "is, of course, to address combination strategies. As for all complex diseases in T1 D [type 1 diabetes], it is obvious that only by combining agents, one may take advantage of synergies in the mode of action, reduce the dosages of single drugs, thereby decreasing side effects." (see page 14, most particularly the bottom of the left column). With regard to administration of autoantigens, Chatenoud et al. disclose that "One promising development in the field of antigen-based therapies was the combination of antigen with adjuvant for vaccination." (see particularly the left column of page 13) and that administration of autoantigen in the correct context is thought to work by expanding the number and/or function of regulatory T cells (see particularly the paragraph spanning pages 2 and 3). Such teachings differ from the instant claimed invention that the use of preproinsulin as a diabetes autoantigen is not disclosed.
The ‘467 document discloses pharmaceutical compositions which contain preproinsulin in combination with an oil-based adjuvant for the treatment of diabetes, with IFA and Montanide ISA beings specifically taught as oil-based adjuvants (see entire document, particularly paragraphs [0005], [0006], [0009], [0026], [0039-0041], [0117], and claims 1-30, most particularly claims 2, 3, and 9). It should be noted that Montanide ISA contains mannide oleate (see for example paragraphs [0113] and [0163]). The ratio of autoantigen to adjuvant in such composition are disclosed as being 50/50 by weight (see for example paragraphs [0069] and [0089]). Such compositions are disclosed as being administered via multiple routes including parenterally, subcutaneously, intramuscularly, and mucosally (see for example paragraphs [0184-0185]). Additionally, fragments of insulin comprising residues 33-47 or SEQ ID NO:1 are explicitly disclosed as preferred embodiments for autoantigens present in such pharmaceutical compositions (see most particularly paragraph [0027]).
Therefore, it would have been obvious to a person of ordinary skill in the art at the time the invention was made to combine CTLA4-Ig in a composition with the Type 1 diabetes autoantigen preproinsulin for use in methods of treating diabetes. The courts have long ruled that "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose .... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). See MPEP 2144.06. Further, Chatenoud et al. explicitly teach the desirability of combination therapies to treat diabetes and that such combinations are expected to act synergistically due to different modes of action resulting in smaller doses of drugs and compared to monotherapy and decreased side effects (see particularly the left column of page 14). It is noted that specific dosages, such as those recited in instant claim 27, are not disclosed by Chatenoud et al. or the ‘467 document. However, the reagents disclosed by Chatenoud et al. are disclosed as being useful in treating diabetes and therefore determining how much of a drug to give to achieve this endpoint is a matter of routine optimization for artisans, as is taught in the ‘467 document (see particularly paragraph [0186]). The courts have long ruled that “[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, the amount of drug in a dose is a results effective variable wherein the does is the “variable” which is correlated with the “result” of successful treatment of the disease in question, namely diabetes. Thus, determining how much drug to use in a therapeutic dose requires no more than routine optimization and thus is prima facie obvious in the absence of evidence to the contrary.
Applicant's arguments filed April 17, 2026 have been fully considered but they are not persuasive. Applicant argues that artisans have been attempting to treat diabetes for a long time, and that with regard to immunization encouraging phase I trials were not replicated in phase II and III human trials. Applicant argues that is because combining costimulatory antagonist with peptide vaccines is challenging and is not taught in the art. Thus applicant believes the rejection should be withdrawn.
Applicant’s arguments are not persuasive. It should be noted that no claims appear to require that the “subject” of the claimed methods is a human. Further, with regards to clinical trials, the working examples of the instant specification are abatacept alone to humans (example 1), chemically synthesizing a peptide antigen (example 2), administering insulin B chain alone to mice (example 3), disclosure of a failure to treat NOD mice with a combination of CTLA4-Ig + insulin B chain (example 4, and note that the first two sentences of paragraph [00130] are “The CTLA4-Ig with human insulin B-chain vaccine combination therapy in fully diabetic NOD mice was not seen to reverse the diabetes in these animals. Thus, the combination therapy did not cure the already diabetic NOD mice”, and administration of insulin B chain alone to humans (example 5). Thus there is no working example disclosed in the specification wherein abatacept + diabetes peptide successfully treated anyone, human or otherwise. Thus applicant arguments concerning an apparent lack of expectation of success, if persuasive, would be equally applicable to the instant claims and teachings of the present specification as the data applicant assert artisans would need to see has not been provided. However, combination of peptides and abatacept are discussed as being successful in the art as readily evidenced by the Marketwired document (of record) and Gray et al. (US 2004/0151725, of record, see entire document most particularly paragraph [0095]). As such, applicant’s arguments are not persuasive and the rejection of record is maintained.
Claims 1-4, 6-15, and 17-19 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Gray et al. (US 2004/0151725) in view of US 2003/0045467.
Gray et al. disclose the construction of CTLA4-Ig fusion proteins and their administration to patients to treat autoimmune diseases (see entire document, particularly the abstract and claims). Compositions containing CTLA4-Ig and pharmaceutically acceptable carriers are disclosed, including oil-based compositions (see particularly paragraphs [0074-0082], most particularly [0078]). It is further disclosed that to treat autoimmune diseases with a known autoantigen, it is desirable to coadminister CTLA4-Ig in combination with said known autoantigen, and that a disease amenable to such administration of such compositions is diabetes mellitus (see particularly paragraph [0095]). Such compositions are administered by a variety of injectable routes including intravenously and subcutaneously (see for example paragraph [0076]). These teachings differ from the instant claimed invention in that preproinsulin is not disclosed as a known autoantigen in the disease diabetes mellitus.
The ‘467 document discloses pharmaceutical compositions which contain preproinsulin in combination with an oil-based adjuvant for the treatment of diabetes, with IFA and Montanide ISA beings specifically taught as oil-based adjuvants (see entire document, particularly paragraphs [0005], [0006], [0009], [0026], [0039-0041], [0117], and claims 1-30, most particularly claims 2, 3, and 9). It should be noted that Montanide ISA contains mannide oleate (see for example paragraphs [0113] and [0163]). The ratio of autoantigen to adjuvant in such composition are disclosed as being 50/50 by weight (see for example paragraphs [0069] and [0089]). Such compositions are disclosed as being administered via multiple routes including parenterally, subcutaneously, intramuscularly, and mucosally (see for example paragraphs [0184-0185]). Additionally, fragments of insulin comprising residues 33-47 or SEQ ID NO:1 are explicitly disclosed as preferred embodiments for autoantigens present in such pharmaceutical compositions (see most particularly paragraph [0027]).
Therefore, it would have been obvious to a person of ordinary skill in the art at the time the instant application was filed to have made a composition comprising both CTLA4-Ig and preproinsulin. This is because Gray et al. explicitly teach that their CTLA4-Ig is to be coadministered with a known antigen to treat the autoimmune disease diabetes mellitus and the ‘467 document discloses that preproinsulin is an autoantigen in diabetes. Further, the courts have long ruled that “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted). In the instant case, both CTLA4-Ig as well as preproinsulin in IFA are taught in the prior art for treating diabetes.
It is noted that Gray et al. do not disclose specific doses for their CTLA4-Ig fusion proteins, but they do teach that it is routine for artisans to determine an effective dose considering variables such as the disease state, age, weight and sex of a patient to optimize the therapeutic response to their administered fusion protein (see particularly paragraph [0075]). As such, figuring out how much CTLA4-Ig to place into a therapeutic composition is a results effective variable as artisans will optimize how much drug to put into the composition so that the patient’s disease, in this case diabetes, is effectively treated. Similarly, the ‘467 document also discloses that dosing is subject to routine optimization by artisans (see particularly paragraph [0186]). It should also be pointed out that the courts have long ruled that “[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). Given that the amount of drug in a dose is correlated with efficacy of disease treatment as discussed above, finding a suitable dose for administration is prima facie obvious in the absence of evidence to the contrary.
Applicant's arguments filed April 17, 2026 have been fully considered but they are not persuasive. Applicant argues “Again, over two decades have passed since the publication of the Gray reference without any CTLA4 based Ig fusion product progressing to FDA regulatory approval for treating Type 1 diabetes. Similarly, a decade has passed since the Examiner's cited combination of Gray and the '467 reference without significant clinical advancement of the cited combination for the treatment of Type 1 diabetes. Given the establised [sic] lack of success in the field (presumably complicated by the chemical incompatability [sic], from solubility perspective, of the required reagents), it's difficult to suggest that one skilled in the art could have merely combined the cited teachings to successfully treat the progression of Type 1 diabetes. Something more is clearly required. Accordingly, the rejection of Claims 1-4, 6-15, and 17-19 are both respectfully traversed and deemed to have been avoided by amendment.”
These arguments are not persuasive. In response to applicant's argument based upon the age of the references, contentions that the reference patents are old are not impressive absent a showing that the art tried and failed to solve the same problem notwithstanding its presumed knowledge of the references. See In re Wright, 569 F.2d 1124, 193 USPQ 332 (CCPA 1977). Additionally, it should be pointed out that the priority date of the instant application goes back over a decade, to 6/27/2012 when great-great-grandparent application 13/534,571 (now issued US patent 8,735,359) was originally filed. Applicant has argued that in the past decade there has been no significant clinical advancement of the cited combination, i.e. CTLA4-Ig/abatacept + diabetes autoantigen, even though methods of administering CTLA4-Ig + diabetes peptide was issued to applicant on May 27, 2014 as US 8,735,359. It cannot be stressed enough that applicant’s arguments indicate that applicant’s own issued patent in the instant chain of priority (all continuations) drawn to a different species of diabetes autoantigen is “not clinically significant”. Thus, applicant’s arguments about lack of success are unpersuasive as by applicant’s own admission the prior art demonstrates the same level of success as that which is presently disclose. The rejection is maintained.
Claim 5 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Gray et al. (US 2004/0151725) in view of US 2003/0045467 as applied to claims 1-4, 6-15, and 17-19 above, and further in view of Chatenoud et al.
The inventions rendered obvious by the teachings of Gray et al. and the '467 document have been discussed above and differ from the instant claimed invention in that the CTLA4-Ig constructs of Gray et al are not taught as being abatacept.
Chatenoud et al. disclose that Abatacept (CTLA4-Ig) has been used in clinical trials for the treatment of diabetes mellitus (see entire document, particularly the abstract and page 6). It is also disclosed that the best way to treat diabetes "is, of course, to address combination strategies. As for all complex diseases in T1 D it is obvious that only by combining agents, one may take advantage of synergies in the mode of action, reduce the dosages of single drugs, thereby decreasing side effects." (see page 14, most particularly the bottom of the left column).
Therefore, it would have been obvious to a person of ordinary skill in the art at the time the instant invention was made to substitute abatacept for the CTLA4-Ig used in the compositions and methods of administration rendered obvious by the teachings of Gray et al. and the ‘467 document since abatacept has the advantage of being successfully used in human therapy as taught by Chatenoud et al.
Applicant's arguments filed April 17, 2026 have been fully considered but they are not persuasive. Applicant argues that the base obviousness rejection is not tenable and that the additional teachings of Chatenoud et al. fail to rectify its deficiencies.
This argument has bene considered and is not persuasive as the base obviousness rejection has been maintained. See above.
Claim 16 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Cohen et al. (US Patent 8,497,247) in view of US 2003/0045467 as applied to claims 1-15 and 17-19 above, and further in view of Orban et al.
The inventions rendered obvious by the collective teachings of the prior art have been discussed above and differ from that which is presently claimed in that measuring the level of insulin C peptide in blood is not taught as a marker for monitoring disease progression.
Orban et al. disclose that measuring the level of C peptide in patient blood can be used to monitor the course of disease progression in diabetes patients (see entire document, particularly the abstract, section 2.3 titled Study Design, Figure 1, and the discussion section). It should be noted that C peptide is a fragment or preproinsulin, and that the amount of C peptide is a proxy for the amount of insulin being produced by the patient.
Therefore it would have been obvious to artisans to include a step of monitoring disease progression by measuring C peptide in blood samples as such assays are routinely done for diabetic patients. Performing such assays would provide artisans with information as to how the patient was responding to the treatment methods rendered obvious by the teachings of the prior art.
Applicant's arguments filed April 17, 2026 have been fully considered but they are not persuasive. Applicant argues that the base obviousness rejection is not tenable and that the additional teachings of Orban et al. fail to rectify its deficiencies.
This argument has bene considered and is not persuasive as the base obviousness rejection has been maintained. See above.
Claim 16 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Marketwired in view of Cohen et al. (US Patent 8,497,247) and in view of US 2003/0045467 as applied to claims 1-15 and 17-19 above, and further in view of Orban et al.
The inventions rendered obvious by the collective teachings of the prior art have been discussed above and differ from that which is presently claimed in that measuring the level of insulin C peptide in blood is not taught as a marker for monitoring disease progression.
Orban et al. disclose that measuring the level of C peptide in patient blood can be used to monitor the course of disease progression in diabetes patients (see entire document, particularly the abstract, section 2.3 titled Study Design, Figure 1, and the discussion section). It should be noted that C peptide is a fragment or preproinsulin, and that the amount of C peptide is a proxy for the amount of insulin being produced by the patient.
Therefore it would have been obvious to artisans to include a step of monitoring disease progression by measuring C peptide in blood samples as such assays are routinely done for diabetic patients. Performing such assays would provide artisans with information as to how the patient was responding to the treatment methods rendered obvious by the teachings of the prior art.
Applicant's arguments filed April 17, 2026 have been fully considered but they are not persuasive. Applicant argues that the base obviousness rejection is not tenable and that the additional teachings of Orban et al. fail to rectify its deficiencies.
This argument has bene considered and is not persuasive as the base obviousness rejection has been maintained. See above.
Claim 16 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Chatenoud et al. in view of US 2003/0045467 as applied to claims 1-15 and 17-19 above, and further in view of Orban et al.
The inventions rendered obvious by the collective teachings of the prior art have been discussed above and differ from that which is presently claimed in that measuring the level of insulin C peptide in blood is not taught as a marker for monitoring disease progression.
Orban et al. disclose that measuring the level of C peptide in patient blood can be used to monitor the course of disease progression in diabetes patients (see entire document, particularly the abstract, section 2.3 titled Study Design, Figure 1, and the discussion section). It should be noted that C peptide is a fragment or preproinsulin, and that the amount of C peptide is a proxy for the amount of insulin being produced by the patient.
Therefore it would have been obvious to artisans to include a step of monitoring disease progression by measuring C peptide in blood samples as such assays are routinely done for diabetic patients. Performing such assays would provide artisans with information as to how the patient was responding to the treatment methods rendered obvious by the teachings of the prior art.
Applicant's arguments filed April 17, 2026 have been fully considered but they are not persuasive. Applicant argues that the base obviousness rejection is not tenable and that the additional teachings of Orban et al. fail to rectify its deficiencies.
This argument has bene considered and is not persuasive as the base obviousness rejection has been maintained. See above.
Claim 16 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Gray et al. (US 2004/0151725) in view of US 2003/0045467 as applied to claims 1-4, 6-15 and 17-19 above, and further in view of Orban et al.
The inventions rendered obvious by the collective teachings of the prior art have been discussed above and differ from that which is presently claimed in that measuring the level of insulin C peptide in blood is not taught as a marker for monitoring disease progression.
Orban et al. disclose that measuring the level of C peptide in patient blood can be used to monitor the course of disease progression in diabetes patients (see entire document, particularly the abstract, section 2.3 titled Study Design, Figure 1, and the discussion section). It should be noted that C peptide is a fragment or preproinsulin, and that the amount of C peptide is a proxy for the amount of insulin being produced by the patient.
Therefore it would have been obvious to artisans to include a step of monitoring disease progression by measuring C peptide in blood samples as such assays are routinely done for diabetic patients. Performing such assays would provide artisans with information as to how the patient was responding to the treatment methods rendered obvious by the teachings of the prior art.
Applicant's arguments filed April 17, 2026 have been fully considered but they are not persuasive. Applicant argues that the base obviousness rejection is not tenable and that the additional teachings of Orban et al. fail to rectify its deficiencies.
This argument has bene considered and is not persuasive as the base obviousness rejection has been maintained. See above.
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 claims at issue 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); and 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 a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this 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 §§ 706.02(l)(1) - 706.02(l)(3) 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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/forms/. The 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 http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
The office action mailed October 17, 2025 set forth the following non-statutory double patenting rejections:
Claims 1 and 3-12 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 8,735,359. Although the claims at issue are not identical, they are not patentably distinct from each other because the issued clams anticipate that which is presently claimed.
Specifically, the application which gave rise to the ‘359 patent is the great-great-grandparent of the instant application. The issued claims recite methods of treating diabetes by administering preproinsulin and a CTLA4 fusion protein to a subject (see all issued claims, particularly issued claim 1). Notably the CTLA4 fusion protein is recited as being abatacept (issued claim 2), and the drugs are recited as being present in the oil-based carriers IFA and Montanide ISA (see issued claim 5). As such the issued claims are narrower in scope than that which is presently claimed.
Claims 2, 13-15, and 17-19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 8,735,359 as applied to claims 1 and 3-12 above, and further in view of Cohen et al. (US Patent 8,497,247) and in view of US 2003/0045467.
The inventions anticipated by the claims of the ‘359 patent have been discussed above and differ from the instant claimed inventions in that the issued claims do not explicitly recite routes by which the compositions are administered or the amounts of various ingredients in the administered compositions.
Cohen et al. disclose the administration of CTLA4-Ig for the treatment of diabetes mellitus (see entire document, particularly the abstract and claims). The amount of CTLA4-Ig which is to be administered is disclosed in both an individualized basis in mg/kg as well as incremental dosing such as 500 mg for a subject weighing less than 60 kg, 750 mg for a subject weighing 60-100 kg, and 1000 mg for subjects over 100kg (see particularly columns 19 and 20 and columns 31-33) and note that such doses anticipate that presently recited in instant claim 30. Such administrations are disclosed as occurring via numerous routes including intravenous, intramuscular, and subcutaneously either alone or in combination with additional therapeutic agents (see particularly column 39). The use of carriers in pharmaceutical compositions, including oil-based, are disclosed by Cohen et al. (see particularly column 34). It should be noted that the '247 patent to Cohen et al. claims continuity to applications disclosed by paragraph [0029] of the instant specification as disclosing abatacept and thus based upon the evidence presently of record the CTLA4-Ig of Cohen et al. is abatacept. Administration of CTLA4-Ig in combination with additional therapeutic agents is disclosed (see column 40 for example).
The ‘467 document discloses pharmaceutical compositions which contain preproinsulin in combination with an oil-based adjuvant for the treatment of diabetes, with IFA and Montanide ISA beings specifically taught as oil-based adjuvants (see entire document, particularly paragraphs [0005], [0006], [0009], [0026], [0039-0041], [0117], and claims 1-30, most particularly claims 2, 3, and 9). It should be noted that Montanide ISA contains mannide oleate (see for example paragraphs [0113] and [0163]). The ratio of autoantigen to adjuvant in such composition are disclosed as being 50/50 by weight (see for example paragraphs [0069] and [0089]). Such compositions are disclosed as being administered via multiple routes including parenterally, subcutaneously, intramuscularly, and mucosally (see for example paragraphs [0184-0185]).
Therefore, it would have been obvious to a person of ordinary skill in the art at the time the invention was filed to practice the issued ‘359 patent administration methods wherein the abatacept and preproinsulin are in either in the same or separate compositions at staggered or simultaneous times. Issued claim 1 recites that administering both active ingredients in a pharmaceutically acceptable carrier and logically there are only two options, namely administering the reagents separately or in the same composition. Further, it both active ingredients are present in the same composition it is impossible to administer them in any manner other than simultaneous. Separate compositions realistically are usually sequential although theoretically they can be administered simultaneously if two people are doing the administration, for example the first person administers the abatacept syringe while the second administers the preproinsulin syringe with both administrations taking place on the count of three. Even in the absence of such common sense, Cohen et al. teach that CTLA4-Ig is to be used to treat diabetes and combined with other agents known to treat the autoimmune disease, while the teachings of the ‘467 document disclose that preproinsulin is to be administered in conjunction with oil based adjuvants including IFA for the treatment of diabetes. Applicant is reminded that "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose .... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). See MPEP 2144.06.
It is noted that neither the issued claims nor the ‘467 document appear to disclose specific doses for preproinsulin which are administered to treat diabetes. However, optimizing the dose as well as the timing of a therapeutic agent to best treat a disease is a routine and common practice for artisans as is acknowledged by the ‘467 document (see particularly paragraph [0186]) and thus determining how much autoantigen to combine with the CTLA4-Ig such as abatacept is a matter of optimizing a results effective variable, with the “variable” being the dose and the “result” being patient treatment/outcome. It should be pointed out that the courts have long ruled that “[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). Given that the amount of drug in a dose is correlated with efficacy of disease treatment as discussed above, finding a suitable dose for administration is prima facie obvious in the absence of evidence to the contrary.
Claim 16 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 8,735,359 as applied to claims 1 and 3-12 above, and further in view of Orban et al.
The inventions of the patented claims have been discussed above and differ from that which is presently claimed in that measuring the level of insulin C peptide in blood is not taught as a marker for monitoring disease progression.
Orban et al. disclose that measuring the level of C peptide in patient blood can be used to monitor the course of disease progression in diabetes patients (see entire document, particularly the abstract, section 2.3 titled Study Design, Figure 1, and the discussion section). It should be noted that C peptide is a fragment or preproinsulin, and that the amount of C peptide is a proxy for the amount of insulin being produced by the patient.
Therefore it would have been obvious to artisans to include a step of monitoring disease progression by measuring C peptide in blood samples as such assays are routinely done for diabetic patients when performing the methods of the issued patent. Performing such assays would provide artisans with information as to how the patient was responding to the treatment methods of the issued claims.
Claims 1-15 and 17-19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 10,233,242 in view of Cohen et al. (US Patent 8,497,247) and in view of US 2003/0045467.
The issued claims of the ‘242 patent recite methods of treating diabetes by administering a composition comprising CTLA4 fusion proteins including abatacept present in water-in-oil compositions (see all issued claims, particularly 1 and 2). Such compositions are recited as being administered intravenously as well as at various masses of drug. The issued claims differ from what is presently claimed in that the issued claims do not recite administration of preproinsulin.
Cohen et al. disclose the administration of CTLA4-Ig for the treatment of diabetes mellitus (see entire document, particularly the abstract and claims). The amount of CTLA4-Ig which is to be administered is disclosed in both an individualized basis in mg/kg as well as incremental dosing such as 500 mg for a subject weighing less than 60 kg, 750 mg for a subject weighing 60-100 kg, and 1000 mg for subjects over 100kg (see particularly columns 19 and 20 and columns 31-33) and note that such doses anticipate that presently recited in instant claim 30. Such administrations are disclosed as occurring via numerous routes including intravenous, intramuscular, and subcutaneously either alone or in combination with additional therapeutic agents (see particularly column 39). The use of carriers in pharmaceutical compositions, including oil-based, are disclosed by Cohen et al. (see particularly column 34).
The ‘467 document discloses pharmaceutical compositions which contain preproinsulin in combination with an oil-based adjuvant for the treatment of diabetes, with IFA and Montanide ISA beings specifically taught as oil-based adjuvants (see entire document, particularly paragraphs [0005], [0006], [0009], [0026], [0039-0041], [0117], and claims 1-30, most particularly claims 2, 3, and 9). It should be noted that Montanide ISA contains mannide oleate (see for example paragraphs [0113] and [0163]). The ratio of autoantigen to adjuvant in such composition are disclosed as being 50/50 by weight (see for example paragraphs [0069] and [0089]). Such compositions are disclosed as being administered via multiple routes including parenterally, subcutaneously, intramuscularly, and mucosally (see for example paragraphs [0184-0185]).
Therefore, it would have been obvious to a person of ordinary skill in the art at the time the invention was filed to modify the issued ‘242 patent administration methods to include the administration of preproinsulin. This is because Cohen et al. teach that CTLA4-Ig is to be administered to treat diabetes and combined with other agents known to treat the autoimmune disease, and the teachings of the ‘467 document that preproinsulin is to be administered in conjunction with oil based adjuvants including IFA for the treatment of diabetes. Applicant is reminded that "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose .... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). See MPEP 2144.06.
It should be pointed out that when administering two active therapeutic agents, logically there are only two options, namely administering the reagents separately or in the same composition. Further, it both active ingredients are present in the same composition it is impossible to administer them in any manner other than simultaneous. Separate compositions realistically are usually sequential although theoretically they can be administered simultaneously if two people are doing the administration as was discussed in more depth elsewhere in in this office action, and such information would be well known to ordinary artisans who are medical professionals well versed in the administration of therapeutic agents to best meet the needs of their patients.
It is noted that neither the issued claims nor the ‘467 document appear to disclose specific doses for preproinsulin which are administered to treat diabetes. However, optimizing the dose as well as the timing of a therapeutic agent to best treat a disease is a routine and common practice for artisans as is acknowledged by the ‘467 document (see particularly paragraph [0186]) and thus determining how much autoantigen to combine with the CTLA4-Ig such as abatacept is a matter of optimizing a results effective variable, with the “variable” being the dose and the “result” being patient treatment/outcome. It should be pointed out that the courts have long ruled that “[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). Given that the amount of drug in a dose is correlated with efficacy of disease treatment as discussed above, finding a suitable dose for administration is prima facie obvious in the absence of evidence to the contrary.
Claim 16 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 10,233,242 in view of Cohen et al. (US Patent 8,497,247) and in view of US 2003/0045467 as applied to claims 1-15 and 17-19, and further in view of Orban et al.
The obvious variations of the issued claims based upon the teachings of the prior art have been discussed above and differ from that which is presently claimed in that measuring the level of insulin C peptide in blood is not taught as a marker for monitoring disease progression.
Orban et al. disclose that measuring the level of C peptide in patient blood can be used to monitor the course of disease progression in diabetes patients (see entire document, particularly the abstract, section 2.3 titled Study Design, Figure 1, and the discussion section). It should be noted that C peptide is a fragment or preproinsulin, and that the amount of C peptide is a proxy for the amount of insulin being produced by the patient.
Therefore it would have been obvious to artisans to include a step of monitoring disease progression by measuring C peptide in blood samples as such assays are routinely done for diabetic patients when performing the methods rendered obvious by the combination of the ‘242 methods in view of the prior art. The addition of such a step would provide artisans with information as to how the patient was responding to the diabetes treatment methods.
Claims 1-15 and 17-19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11,286,303 in view of Cohen et al. (US Patent 8,497,247) and in view of US 2003/0045467.
The issued claims of the ‘303 patent recite methods of treating diabetes by administering a composition comprising CTLA4 fusion proteins present in water-in-oil compositions comprising IFA or Montanide ISA (see all issued claims, particularly claim 1). Such compositions are recited as being administered at various times and masses of drug. Notably, CTLA4 fusion proteins are recited as being fusions to immunoglobulin (see for example issued claims 1 and 4). The issued claims differ from what is presently claimed in that the issued claims do not recite administration of preproinsulin.
Cohen et al. disclose the administration of CTLA4-Ig for the treatment of diabetes mellitus (see entire document, particularly the abstract and claims). The amount of CTLA4-Ig which is to be administered is disclosed in both an individualized basis in mg/kg as well as incremental dosing such as 500 mg for a subject weighing less than 60 kg, 750 mg for a subject weighing 60-100 kg, and 1000 mg for subjects over 100kg (see particularly columns 19 and 20 and columns 31-33) and note that such doses anticipate that presently recited in instant claim 30. Such administrations are disclosed as occurring via numerous routes including intravenous, intramuscular, and subcutaneously either alone or in combination with additional therapeutic agents (see particularly column 39). The use of carriers in pharmaceutical compositions, including oil-based, are disclosed by Cohen et al. (see particularly column 34).
The ‘467 document discloses pharmaceutical compositions which contain preproinsulin in combination with an oil-based adjuvant for the treatment of diabetes, with IFA and Montanide ISA beings specifically taught as oil-based adjuvants (see entire document, particularly paragraphs [0005], [0006], [0009], [0026], [0039-0041], [0117], and claims 1-30, most particularly claims 2, 3, and 9). It should be noted that Montanide ISA contains mannide oleate (see for example paragraphs [0113] and [0163]). The ratio of autoantigen to adjuvant in such composition are disclosed as being 50/50 by weight (see for example paragraphs [0069] and [0089]). Such compositions are disclosed as being administered via multiple routes including parenterally, subcutaneously, intramuscularly, and mucosally (see for example paragraphs [0184-0185]).
Therefore, it would have been obvious to a person of ordinary skill in the art at the time the invention was filed to modify the issued ‘303 patent administration methods to include the administration of preproinsulin. This is because Cohen et al. teach that CTLA4-Ig is to be administered to treat diabetes and combined with other agents known to treat the autoimmune disease, and the teachings of the ‘467 document that preproinsulin is to be administered in conjunction with oil based adjuvants including IFA for the treatment of diabetes. Applicant is reminded that "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose .... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). See MPEP 2144.06.
It should be pointed out that when administering two active therapeutic agents, logically there are only two options, namely administering the reagents separately or in the same composition. Further, it both active ingredients are present in the same composition it is impossible to administer them in any manner other than simultaneous. Separate compositions realistically are usually sequential although theoretically they can be administered simultaneously if two people are doing the administration as was discussed in more depth elsewhere in in this office action, and such information would be well known to ordinary artisans who are medical professionals well versed in the administration of therapeutic agents to best meet the needs of their patients.
It is noted that neither the issued claims nor the ‘467 document appear to disclose specific doses for preproinsulin which are administered to treat diabetes. However, optimizing the dose as well as the timing of a therapeutic agent to best treat a disease is a routine and common practice for artisans as is acknowledged by the ‘467 document (see particularly paragraph [0186]) and thus determining how much autoantigen to combine with the CTLA4-Ig such as abatacept is a matter of optimizing a results effective variable, with the “variable” being the dose and the “result” being patient treatment/outcome. It should be pointed out that the courts have long ruled that “[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). Given that the amount of drug in a dose is correlated with efficacy of disease treatment as discussed above, finding a suitable dose for administration is prima facie obvious in the absence of evidence to the contrary.
Claim 16 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11,286,303 in view of Cohen et al. (US Patent 8,497,247) and in view of US 2003/0045467 as applied to claims 1-15 and 17-19, and further in view of Orban et al.
The obvious variations of the issued claims based upon the teachings of the prior art have been discussed above and differ from that which is presently claimed in that measuring the level of insulin C peptide in blood is not taught as a marker for monitoring disease progression.
Orban et al. disclose that measuring the level of C peptide in patient blood can be used to monitor the course of disease progression in diabetes patients (see entire document, particularly the abstract, section 2.3 titled Study Design, Figure 1, and the discussion section). It should be noted that C peptide is a fragment or preproinsulin, and that the amount of C peptide is a proxy for the amount of insulin being produced by the patient.
Therefore it would have been obvious to artisans to include a step of monitoring disease progression by measuring C peptide in blood samples as such assays are routinely done for diabetic patients when performing the methods rendered obvious by the combination of the ‘303 methods in view of the prior art. The addition of such a step would provide artisans with information as to how the patient was responding to the diabetes treatment methods.
Claims 1-15 and 17-19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 8,652,488 in view of Cohen et al. (US 8,497,247) and in view of US 2003/0045467.
The issued claims recite compositions which comprise a fragment of the B-chain of human insulin in combination with oil-based adjuvants including Montanide ISA and IFA (see all issued claims, most notably claims 1, 3, 6, and 12). It should be noted that the disclosed utility for such compositions is the treatment of diabetes mellitus (see entire document, particularly the abstract). These claims differ from the instant claimed invention in that CTLA4-Ig is not recited as part of the patented compositions, in that the autoantigen is the B-peptide of insulin rather than the full length sequence of preproinsulin, and that administration to a diabetes patient is not recited. It should be pointed out that the B-peptide is a fragment of preproinsulin.
Cohen et al. disclose the administration of CTLA4-Ig for the treatment of diabetes mellitus (see entire document, particularly the abstract and claims). The amount of CTLA4-Ig which is to be administered is disclosed in both an individualized basis in mg/kg as well as incremental dosing such as 500 mg for a subject weighing less than 60 kg, 750 mg for a subject weighing 60-100 kg, and 1000 mg for subjects over 100kg (see particularly columns 19 and 20 and columns 31-33) and note that such doses anticipate that presently recited in instant claim 30. Such administrations are disclosed as occurring via numerous routes including intravenous, intramuscular, and subcutaneously either alone or in combination with additional therapeutic agents (see particularly column 39). The use of carriers in pharmaceutical compositions, including oil-based, are disclosed by Cohen et al. (see particularly column 34). Administration of CTLA4-Ig in combination with additional therapeutic agents is also disclosed (see column 40 for example) and based upon the evidence of record the CTLA4-Ig fusion protein used by Cohen et al. appears to be abatacept.
The ‘467 document discloses pharmaceutical compositions which contain preproinsulin in combination with an oil-based adjuvant for the treatment of diabetes, with IFA and Montanide ISA beings specifically taught as oil-based adjuvants (see entire document, particularly paragraphs [0005], [0006], [0009], [0026], [0039-0041], [0117], and claims 1-30, most particularly claims 2, 3, and 9). It should be noted that Montanide ISA contains mannide oleate (see for example paragraphs [0113] and [0163]). The ratio of autoantigen to adjuvant in such composition are disclosed as being 50/50 by weight (see for example paragraphs [0069] and [0089]). Such compositions are disclosed as being administered via multiple routes including parenterally, subcutaneously, intramuscularly, and mucosally (see for example paragraphs [0184-0185]).
Therefore, it would have been obvious to a person of ordinary skill in the art at the time the invention was filed to modify the compositions of the issued claims to arrive at the instant claimed invention. Specifically, it would have been obvious to an ordinary artisan that full length preproinsulin could be substituted for the B-chain as they are related (B chain is a fragment of preproinsulin) and both are taught for use in vaccines to treat diabetes, and thus actually administering such a composition to treat diabetes is obvious as that is reason why artisans would make such compositions. It should also be pointed out that the specification of the ‘488 patent and the ‘467 document are identical documents. Thus ordinary artisans would be well aware that preproinsulin was another embodiment which was fully disclosed but not claimed in the ‘488 patent which is highly related as the autoantigen peptide present in the issued compositions is present in the longer sequence of preproinsulin. Additionally, it would also have been obvious to combine such autoantigen in IFA compositions with the CTLA4-Ig compositions of Cohen et al. as both were known to be useful in treating diabetes. Applicant is reminded that "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose .... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). See MPEP 2144.06. Further, as has been discussed elsewhere in this office action, determining the dose of drug in a composition is an exercise in optimizing a results effective variable, an obvious and routine occurrence for ordinary artisans in the absence of evidence to the contrary.
It is also noted that the issued claims are directed toward products whereas the instant claims are directed to therapeutic administration methods. However, the application that gave rise to the ‘488 patent is not a progenitor of the instant application, and recent court decisions such as Pfizer v. Teva and Amgen Inc. v. F. Hoffman-La-Roche Ltd. Have made it abundantly clear that “the § 121 safe harbor provision does not protect continuation applications or patents descending from only continuation applications. The statute on its face applies only to divisional applications, and a continuation application, like a continuation-in-part application, is not a divisional application.” As there is no relationship between the instant application and that which gave rise to the ‘488 patent as evidenced by the filing receipt mailed 11/15/2023 for the instant application the rejection has been set forth.
Claim 16 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 8,652,488 in view of Cohen et al. (US 8,497,247) and in view of US 2003/0045467 as applied to claims 1-15 and 17-19, and further in view of Orban et al.
The obvious variations of the issued claims based upon the teachings of the prior art have been discussed above and differ from that which is presently claimed in that measuring the level of insulin C peptide in blood is not taught as a marker for monitoring disease progression.
Orban et al. disclose that measuring the level of C peptide in patient blood can be used to monitor the course of disease progression in diabetes patients (see entire document, particularly the abstract, section 2.3 titled Study Design, Figure 1, and the discussion section). It should be noted that C peptide is a fragment or preproinsulin, and that the amount of C peptide is a proxy for the amount of insulin being produced by the patient.
Therefore it would have been obvious to artisans to include a step of monitoring disease progression by measuring C peptide in blood samples as such assays are routinely done for diabetic patients when performing the methods rendered obvious by the combination of the ‘488 methods in view of the prior art. The addition of such a step would provide artisans with information as to how the patient was responding to the diabetes treatment methods.
Claims 1-4, 6-15, and 17-19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 8,652,488 in view of Gray et al. (US 2004/0151725) and in view of US 2003/0045467.
The issued claims recite compositions which comprise a fragment of the B-chain of human insulin in combination with oil-based adjuvants including Montanide ISA and IFA (see all issued claims, most notably claims 1, 3, 6, and 12). It should be noted that the disclosed utility for such compositions is the treatment of diabetes mellitus (see entire document, particularly the abstract). These claims differ from the instant claimed invention in that CTLA4-Ig is not recited as part of the patented compositions and in that the autoantigen is the B-peptide of insulin rather than the full length sequence of preproinsulin. It should be pointed out that the B-peptide is a fragment of preproinsulin.
Gray et al. disclose the construction of CTLA4-Ig fusion proteins and their administration to patients to treat autoimmune diseases (see entire document, particularly the abstract and claims). Compositions containing CTLA4-Ig and pharmaceutically acceptable carriers are disclosed, including oil-based compositions (see particularly paragraphs [0074-0082], most particularly [0078]). It is further disclosed that to treat autoimmune diseases with a known autoantigen, it is desirable to coadminister CTLA4-Ig in combination with said known autoantigen, and that a disease amenable to such administration of such compositions is diabetes mellitus (see particularly paragraph [0095]). Such compositions are administered by a variety of injectable routes including intravenously and subcutaneously (see for example paragraph [0076]). These teachings differ from the instant claimed invention in that preproinsulin is not disclosed as a known autoantigen in the disease diabetes mellitus.
The ‘467 document discloses pharmaceutical compositions which contain preproinsulin in combination with an oil-based adjuvant for the treatment of diabetes, with IFA and Montanide ISA beings specifically taught as oil-based adjuvants (see entire document, particularly paragraphs [0005], [0006], [0009], [0026], [0039-0041], [0117], and claims 1-30, most particularly claims 2, 3, and 9). It should be noted that Montanide ISA contains mannide oleate (see for example paragraphs [0113] and [0163]). The ratio of autoantigen to adjuvant in such composition are disclosed as being 50/50 by weight (see for example paragraphs [0069] and [0089]). Such compositions are disclosed as being administered via multiple routes including parenterally, subcutaneously, intramuscularly, and mucosally (see for example paragraphs [0184-0185]).
Therefore, it would have been obvious to a person of ordinary skill in the art at the time the invention was filed to modify the compositions of the issued claims to arrive at the instant claimed invention. Specifically, it would have been obvious to an ordinary artisan that full length preproinsulin could be substituted for the B-chain as they are related (B chain is a fragment of preproinsulin) and both are taught for use in vaccines to treat diabetes, and thus actually administering such a composition to treat diabetes is obvious as that is reason why artisans would make such compositions. It should also be pointed out that the specification of the ‘488 patent and the ‘467 document are identical documents. Thus ordinary artisans would be well aware that preproinsulin was another embodiment which was fully disclosed but not claimed in the ‘488 patent which is highly related as the autoantigen peptide present in the issued compositions is present in the longer sequence of preproinsulin. Additionally, it would also have been obvious to combine such autoantigen in IFA compositions with the CTLA4-Ig compositions of Gray et al. This is because Gray et al. explicitly teach that their CTLA4-Ig is to be coadministered with a known antigen to treat the autoimmune disease diabetes mellitus and as discussed above insulin peptides, including preproinsulin, were known in the art for treating diabetes. Applicant is reminded that the courts have long ruled that “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted). Further, as has been discussed elsewhere in this office action, determining the dose of drug in a composition used to treat a disease is an exercise in optimizing a results effective variable, an obvious and routine occurrence for ordinary artisans in the absence of evidence to the contrary.
It is also noted that the issued claims are directed toward products whereas the instant claims are directed to therapeutic administration methods. However, the application that gave rise to the ‘488 patent is not a progenitor of the instant application, and recent court decisions such as Pfizer v. Teva and Amgen Inc. v. F. Hoffman-La-Roche Ltd. Have made it abundantly clear that “the § 121 safe harbor provision does not protect continuation applications or patents descending from only continuation applications. The statute on its face applies only to divisional applications, and a continuation application, like a continuation-in-part application, is not a divisional application.” As there is no relationship between the instant application and that which gave rise to the ‘488 patent as evidenced by the filing receipt mailed 11/15/2023 for the instant application the rejection has been set forth.
Claim 16 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 8,652,488 in view of Gray et al. (US 2004/0151725) and in view of US 2003/0045467 as applied to claims 1-4, 6-15, and 17-19, and further in view of Orban et al.
The obvious variations of the issued claims based upon the teachings of the prior art have been discussed above and differ from that which is presently claimed in that measuring the level of insulin C peptide in blood is not taught as a marker for monitoring disease progression.
Orban et al. disclose that measuring the level of C peptide in patient blood can be used to monitor the course of disease progression in diabetes patients (see entire document, particularly the abstract, section 2.3 titled Study Design, Figure 1, and the discussion section). It should be noted that C peptide is a fragment or preproinsulin, and that the amount of C peptide is a proxy for the amount of insulin being produced by the patient.
Therefore it would have been obvious to artisans to include a step of monitoring disease progression by measuring C peptide in blood samples as such assays are routinely done for diabetic patients when performing the methods rendered obvious by the combination of the ‘488 methods in view of the prior art. The addition of such a step would provide artisans with information as to how the patient was responding to the diabetes treatment methods.
Applicant's arguments filed April 17, 2026 have been fully considered but they are not persuasive. Applicant argues “If still necessary, after patentable subject matter has been identified in the present application, a timely filed terminal disclaimer (and request for reconsideration of the prior Office action) will be submitted in response to a pending obviousness type double patenting rejection.”
It should be noted that as discussed above, issues in addition to double patenting remain. Further, the only way “patentable subject matter [can be] identified” is if ALL grounds of rejection and objection are overcome, with such grounds necessarily encompassing NSDP. Given that applicant has not addressed the issues raised in the rejections set forth in the prior office action they are retained for the reasons of record.
No claims are allowable.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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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Michael Szperka
Primary Examiner
Art Unit 1641
/MICHAEL SZPERKA/ Primary Examiner, Art Unit 1644
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