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 .
DETAILED ACTION
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.
Applicant's submission filed on 3/18/2026 has been entered. Applicant indicates on the Request for Continued Examination (RCE) Transmittal, that the response of 3/18/2026 be considered.
Claim status
Applicant has amended Claims 1, 9, 14, and 16.
Claims 1-3, 7-9, 11-12, 14-18 are under consideration.
Objection to Specification
The specification is objected to because this application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821 (a)(1) and (a)(2), wherein strands of four or more amino acids or ten or more nucleotides are required to be identified by a sequence identifier. However, this application fails to comply with the requirements of 37 CFR 1.821 through 1.825 because sequences are set forth in the specification at pgs.4-5, p.6, line 21, and p.21 lack sequence identifiers. If the sequences are already present in the sequence listing, it would be remedial to amend the specification to include the appropriate sequence identifiers. Applicants are required to comply with all of the requirements of 37 CFR 1.821 - 1.825.
Furthermore, it is noted that the “p35-F” primer (i.e., SEQ ID NO:9) appears to have a gap in the sequence.
Furthermore, on p. 21 the specification states the “ns-p40, which nucleotide sequence was shown in SEQ NO ID: 5”, where in SEQ ID NO: 5 is an amino acid sequence.
Finally, the disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (p. 20, line 14). Applicant is required to amend or delete the embedded hyperlink and/or other form of browser-executable code. For example, “http” can be replaced with “hypertext transfer protocol”. See MPEP § 608.01.
Any response to this office action that fails to meet all of these requirements will be considered non-responsive. The nature of the noncompliance with the requirements of 37 C.F.R. 1.821 through 1.825 did not preclude the examination of the application on the merits, the results of which are communicated below.
New Claim Rejections - 35 USC § 112(a)
(Written Description)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 8-9 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Dependent claim 8 encompasses a genus of methods for treating a disease associated with IL-12 (i.e., a disease that can be treated or prevented by the use of IL-12) comprising administering an oncolytic virus encoding a non-secretory IL-12 comprising a p40 subunit consisting of SEQ ID NO: 4, wherein the non-secretory IL-12 comprising or consists of SEQ ID NO:2 or any variant thereof.
Dependent claim 9 encompasses a genus of methods wherein the variant of the non-secretory IL-12 is between about 60% to 99.9% identical to SEQ ID NO:2. Note that because independent claim 1 requires that the human p40 section of SEQ ID NO:2 (approximately 307 aa out of 515 total) is fixed as SEQ ID NO:4, the claimed variations in the linker and p35 sections of SEQ ID NO:2 indicat that 206 amino acids (i.e., 40% of 515) of the remaining 208 amino acids (i.e., 515-307) can be varied, thereby producing a IL-12 linker and p30 subunit with as little as 1% identity with linker and p35 subunit of SEQ ID NO:2 .
Under the written description guidelines (see MPEP 2163) the Examiner is directed to determine whether one skilled in the art would recognize that the Applicant was in possession of the claimed invention as a whole at the time of filing. The following considerations are critical to this determination.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. An original claim may lack written description support when (1) the claim defines the invention in functional language specifying a desired result but the disclosure fails to sufficiently identify how the function is performed or the result is achieved or (2) a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). The written description requirement is not necessarily met when the claim language appears in ipsis verbis in the specification. "Even if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed. The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement." Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002).
Accordingly, to satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.
ACTUAL REDUCTION TO PRACTICE
In regard to claims 8 and 9 encompassing methods comprising any variant of SEQ ID NO: 2, the specification only provides methods of treating subject with oncolytic viruses that comprise SEQ ID NO:2, but no variants thereof. Furthermore, the specification provides no methods for determining variants of SEQ ID NO:2, wherein the linker or p35 subunit is varied for up to 206 amino acids (i.e., 60% identical to SEQ ID NO: 2), thereby producing a IL-12 linker and p30 subunit with as little as 1% identity with linker and p35 subunit of SEQ ID NO:2 .
Accordingly, Applicant did not demonstrate a reduction to practice of a method of treating a IL-12 responsive disease with any variant of SEQ ID NO: 2, nor did Applicant adequately set forth in terms of distinguishing identifying characteristics as evidenced by other descriptions of the invention that are sufficiently detailed to show that Applicant was in possession of the claimed genus of methods.
DISCLOSURE OF STRUCTURE
The Applicant has provided no examples of a method of treating a disease in a subject comprising administering any variant of SEQ ID NO: 2. Certainly, with the help of a recombinant viral vector facility, a skilled artisan could make variants of SEQ ID NO: 2, wherein the p40 subunit consists of SEQ ID NO: 4, while the linker and p35 subunits have as little as 1% amino acid identity to SEQ ID NO:2. These were known proteins and genes. However, the prior art is silent with respect to methods of treating disease comprising any variant of SEQ ID NO: 2. Furthermore, neither the specification nor the art indicate a relationship between the structure of the claimed genus of variants of SEQ ID NO: 2 and the ability to successfully generate a functional non-secretory IL-12 and treat a disease in a subject.
SUFFICIENT RELEVANT IDENTIFYING CHARACTERISTICS
Methods for treating IL-12 responsive disease such as cancers comprising the administration of oncolytic virus comprising a non-secretory IL-12 that is about 94% identical to SEQ ID NO:2 were known in the prior art (see below), and the skilled artisan could generate variants of SEQ ID NO: 2 that are about 94% identical and still generate a functional non-secretory IL-12.
However, the breadth of the claims encompass a genus of variants of SEQ ID NO:2 that are as low as 60% identical (i.e., 206 out of 515 amino acids can be varied), wherein all of these variations must occur in the 10 amino acid linker and the 198 amino acid p35 region, yet the present specification provides limited guidance and description of methods of treating diseases by administering said genus of variants of SEQ ID NO: 2, therefore the skilled artisan would not know what rational approach to take to make and use the genus of SEQ ID NO: 2 variants comprising the human p40 subunit consisting of SEQ ID NO: 4 with any predictable outcome on IL-12 function. Therefore, it is incumbent on the applicant to provide this nexus between structure and function, in order to be given credit for possession of the claimed genus of methods.
STATE OF THE ART & QUANTITY OF EXPERIMENTATION
The method of practicing the claimed invention is not well established. Although methods for treating IL-12 responsive disease such as cancers comprising the administration of oncolytic virus comprising a non-secretory IL-12 that is about 94% identical to SEQ ID NO:2 were known in the prior art (see Reed et al., (US2017/0291934, filed 9/21/2015, with priority to provisional applications 62/053,628, filed 9/22/2014, and 62/074,875, filed 11/04/2014, see IDS filed 6/02/2022), one of skill in the art would neither expect nor predict a successful outcome to treat a disease in a subject by administering an oncolytic virus comprising any variant of SEQ ID NO: 2.
The following describes the state of the art with respect to variants of SEQ ID NO: 2. For example, Zou et al. (JBC, 1995, 279(11)5864-5871) teaches that the p40 and p35 subunits are species specific to each other, and that this species specificity is determined by the p35 subunit of the IL-12 heterodimer (Abstract). Thus, not any p35 subunit variant that is encompassed by a protein 60% identical to SEQ ID NO: 2 would be expected to form a functional IL-12 with the human p40 subunit consisting of SEQ ID NO: 4.
Applicant has claimed methods to treat an IL-12 responsive disease comprising administering an oncolytic virus comprising any variant of SEQ ID NO:2, yet the specification has not disclosed such variants, has not set forth in terms of distinguishing identifying characteristics as evidenced by other descriptions of the invention that are sufficiently detailed to show that Applicant was in possession of the claimed genus of methods. Furthermore, the state of the art indicated that practicing the claimed method is not well established with the claimed function in successfully matching a p35 subunit with the human p40 subunit to make and use a non-secretory IL-12 with about 60% identity to SEQ ID NO: 2 would require undue experimentation, and one of skill in the art would neither expect nor predict the claimed method of treatment would be successful according to the claimed genus of variants of SEQ ID NO: 2.
CONCLUSION
Therefore, the Examiner concludes that there is insufficient written description of the instantly claimed genus methods comprising any variant of SEQ ID NO: 2. Specifically, there is limited description of the structure-function relationship between the claimed genus of their variations in the p35 subunit and their ability to pair with the human p40 subunit consisting of SEQ ID NO: 4 to for a functional scIL-12 and its ability to treat and IL-12 responsive disease, and the Examiner further concludes a skilled artisan would find the specification inadequately describes the claimed genus of methods.
New Claim Rejections - 35 USC § 112(a)
(Scope of Enablement)
Claims 8-9 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 a method of treating an IL-12 responsive disease comprising administering the non-secretory IL-12 comprising the p40 subunit consisting of nucleic acid sequence of SEQ ID NO:4, wherein non-secretory IL-12 has or consists of the amino acid sequence of SEQ ID NO: 2, or a variant of SEQ ID NO:2 wherein the linker sequence is varied or the p35 subunit is varied to generate a non-secretory IL-12 with 94% identity to SEQ ID NO: 2, does not reasonably provide enablement for methods for any variant of SEQ ID NO: 2. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
SCOPE OF THE INVENTION
Dependent claim 8 encompasses a genus of methods for treating a disease associated with IL-12 (i.e., a disease that can be treated or prevented by the use of IL-12) comprising administering a oncolytic virus encoding a non-secretory IL-12 comprising a p40 subunit consisting of SEQ ID NO: 4, wherein the non-secretory IL-12 comprising or consists of SEQ ID NO:2 or any variant thereof.
Dependent claim 9 encompasses a genus of methods wherein the variant of the non-secretory IL-12 is between about 60% to 99.9% identical to SEQ ID NO:2. Note that because independent claim 1 requires that the human p40 section of SEQ ID NO:2 (approximately 307 aa out of 515 total) is fixed as SEQ ID NO:4, the claimed variation in the linker and p35 sections of SEQ ID NO:2 indicated that 206 amino acids (i.e., 40% of 515) of the remaining 208 amino acids (i.e., 515-307) can be varied, thereby producing a IL-12 linker and p30 subunit with as little as 1% identity with linker and p35 subunit of SEQ ID NO:2.
The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The Court in Wands states: “Enablement is not precluded by the necessity for some 'experimentation.'” Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single simple factual determination, but rather is a conclusion reached by weighing many factual considerations.” (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
The office has analyzed the specification in direct accordance to the factors outlined in In re Wands. MPEP 2164.04 states: "[W]hile the analysis and conclusion of a lack of enablement are based on factors discussed in MPEP 2164.01(a) and the evidence as whole, it is not necessary to discuss each factor in written enablement rejection." These factors will be analyzed, in turn, to demonstrate that one of ordinary skill in the art would have had to perform "undue experimentation" to make and/or use the invention and therefore, Applicant's claims are not enabled commensurate with the scope of the invention.
ACTUAL REDUCTION TO PRACTICE
In regard to claims 8 and 9 encompassing methods comprising any variant of SEQ ID NO: 2, the specification only provides methods of treating subject with oncolytic viruses that comprise SEQ ID NO:2, but no variants thereof. Furthermore, the specification provides no methods for determining variants of SEQ ID NO:2, wherein the linker or p35 subunit is varied for up to 206 amino acids (i.e., 60% identical to the 515 amino acids of SEQ ID NO: 2), thereby producing a IL-12 linker and p30 subunit with as little as 1% identity with linker and p35 subunit of SEQ ID NO:2 .
Accordingly, Applicant did not demonstrate a reduction to practice of a method of treating an IL-12 responsive disease with a variant of SEQ ID NO:2, much less a variant with 60% identity to SEQ ID NO:2 yet comprising the p40 subunit consisting of SEQ ID NO:4.
STATE OF THE ART & QUANTITY OF EXPERIMENTATION
The method of practicing the claimed invention is not well established. Although methods for treating IL-12 responsive disease such as cancers comprising the administration of oncolytic virus comprising a non-secretory IL-12 that is about 94% identical to SEQ ID NO:2 were known in the prior art (see Reed et al., (US2017/0291934, filed 9/21/2015, with priority to provisional applications 62/053,628, filed 9/22/2014, and 62/074,875, filed 11/04/2014, see IDS filed 6/02/2022), one of skill in the art would neither expect nor predict a successful outcome to treat a disease in a subject by administering an oncolytic virus comprising any variant of SEQ ID NO: 2.
The following describes the state of the art with respect to variants of SEQ ID NO: 2. For example, Zou et al. (JBC, 1995, 279(11)5864-5871) teaches that the p40 and p35 subunits are species specific to each other, and that this species specificity is determined by the p35 subunit of the IL-12 heterodimer (Abstract). Thus, not any p35 subunit variant that is encompassed by a protein 60% identical to SEQ ID NO: 2 would be expected to form a functional IL-12 with the human p40 subunit consisting of SEQ ID NO: 4.
Since the prior art at the effective filing date of the present application did not provide guidance for treating IL-12 responsive disease in a subject using any variant of SEQ ID NO: 2, it is incumbent upon the instant specification to do so. The physiological art is recognized as unpredictable (MPEP 2164.03). As set forth in In re Fisher, 166 USPQ 18 (CCPA 1970), compliance with 35 USC 112, first paragraph requires: “That scope of claims must bear a reasonable correlation to scope of enablement provided by specification to persons of ordinary skill in the art; in cases involving predictable factors, such as mechanical or electrical elements, a single embodiment provides broad enablement in the sense that, once imagined, other embodiments can be made without difficulty and their performance characteristics predicted by resort to known scientific laws; in cases involving unpredictable factors, such as most chemical reactions and physiological activity, scope of enablement varies inversely with degree of unpredictability of factors involved.” Moreover, the courts have also stated that reasonable correlation must exist between scope of exclusive right to patent application and scope of enablement set forth in the patent application (27 USPQ2d 1662 Ex parte Maize!.). In view of the foregoing, due to the lack of sufficient guidance provided by the specification regarding the issues set forth above, the state of the relevant art, and the breadth of the claims, it would have required undue experimentation for one skilled in the art to make and use the instant broadly claimed invention.
CONCLUSION
In conclusion, since the art teaches that success of said method is prone to influence by multiple factors, and is highly unpredictable with respect to generating a function IL-12 that comprising a human p40 subunit consisting of SEQ ID NO: 4 with any p35 subunit variant or p35 subunit variant that forms a non-secretory IL-12 with at least 60% identity to SEQ ID NO:2, and the specification does not provide ample guidance with respect to achieving the unexpected results, one would be burdened with undue experimentation to use the claimed invention. Given the breadth of the claims and the limited scope of the specification, an undue quantity of experimentation is require to make and use the invention beyond the scope of treating an IL-12 responsive disease comprising administering the non-secretory IL-12 comprising the p40 subunit consisting of nucleic acid sequence of SEQ ID NO:4, wherein non-secretory IL-12 has or consists of the amino acid sequence of SEQ ID NO: 2, or a variant with 94% identity to SEQ ID NO:2.
Withdrawn 35 USC § 112(b)
The prior rejection of Claim 9 under 35 U.S.C. § 112(b), preAIA 2nd paragraph as being indefinite is withdrawn in light of Applicant’s amendments of Claim 9 to describe the % sequence identity.
New Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 18 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Specifically, claim 18 draws to a method for preparing a “recombinant vector” comprising the nucleic acid of SEQ ID NO:1, which does NOT narrow the scope of claims 1 or 11 where the nucleic acid of SEQ ID NO:1 is already in a recombinant oncolytic viral vector. Essentially, due to the Applicant’s own claim language, the method of making embodiment of claim 18 is excluded from the scope of method of treating embodiments with the oncolytic virus comprising the nucleic acid of SEQ ID NO: 1 of claims 11 and 1. Applicant may cancel the claim, or rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
Declaration under 37 CFR 1.132
The declaration under 37 CFR 1.132 filed by Dr. Yaohe Wang on 3/18/2026 is sufficient to overcome the rejection of instant claims based upon 35 U.S.C 103 over Wang et al. (US 2013/0345295) as set forth in the last Office action for the following reasons: Dr. Wang’s declaration presents comparative data between the 284 amino acid short p40 of Wang (2013) with the claimed 307 amino acid p40 subunit encoded by SEQ ID NO:4, and demonstrate an approximated 20-fold difference in bioactivity between the two constructs in IL-12 receptor activation and signaling (Exhibit A). Thus, Dr. Wang declares that even though one of ordinary skill could have extended the N-terminus of the shorter 284 amino acid p40 subunit to generate the 307 amino acid p40 subunit, there would have been no expectation of this surprising increase in IL-12 activity.
However, it must be noted that although Dr. Wang declaration addresses the prior art suggestion to extend the N-terminus of the short p40 subunit, it does not address the prior art suggestion to reduce the N-terminus of the full-length p40 subunit by removing the signal peptide (see more below).
Withdrawn 35 USC § 102
The prior rejection of Claims 1-3, 8-9, 12, and 15-18 under 35 U.S.C. 102(a)(1)/(a)(2) as being anticipated by Wang et al. (US 2013/0345295, filed 9/02/2013, published 12/26/2013, see IDS filed 6/02/2022) is withdrawn in light of Applicant’s amendment of Claim 1 to remove the capable language.
Withdrawn 35 USC § 103
The prior rejection of Claim 7 under 35 U.S.C. 103 as being unpatentable over Wang et al. (US 2013/0345295, filed 9/02/2013, published 12/26/2013, see IDS filed 6/02/2022), in view of Tang et al., (US2009/0142855, filed 6/30/2006, see IDS filed 6/02/2022) is withdrawn in light of Applicant’s amendment of Claim 1 to remove the capable language.
The prior rejection of Claims 1-3, 8-9, 11-12, 14-18 are under 35 U.S.C. 103 as being unpatentable over Wang et al. (US 2013/0345295, filed 9/02/2013, published 12/26/2013, see IDS filed 6/02/2022), in view of Reed et al., (US2017/0291934, filed 9/21/2015, with priority to provisional applications 62/053,628, filed 9/22/2014, and 62/074,875, filed 11/04/2014, see IDS filed 6/02/2022) is withdrawn in light of Dr. Wang declaration under 37 CFR 1.132 filed on 3/18/2026 declaring that the short p40 construct of Wang et al. (US 2013/0345295) is significantly inferior to the p40 construct consisting of SEQ ID NO:4, and that the unexpected result presented overcome the obviousness to extend the short p40 construct of Wang (US 2013).
The prior rejection of Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (US 2013/0345295, filed 9/02/2013, published 12/26/2013, see IDS filed 6/02/2022), in view of Reed et al., (US2017/0291934, filed 9/21/2015, with priority to provisional applications 62/053,628, filed 9/22/2014, and 62/074,875, filed 11/04/2014, see IDS filed 6/02/2022), as applied to Claim 1, in further view of Tang et al., (US2009/0142855, filed 6/30/2006, see IDS filed 6/02/2022) is withdrawn in light of Dr. Wang declaration under 37 CFR 1.132 filed on 3/18/2026.
New Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-3, 8-9, 11-12, 14-18 are under 35 U.S.C. 103 as being unpatentable over Reed et al., (US2017/0291934, filed 9/21/2015, with priority to provisional applications 62/053,628, filed 9/22/2014, and 62/074,875, filed 11/04/2014, see IDS filed 6/02/2022) in view of Poutou et al. (Gene Therapy, 2015, 22: 696-706, published on-line 5/21/2015)
With respect to claims 1 and 16, Reed teaches methods and compositions for treating a disease by administering a recombinant vector comprising the nucleotide sequence encoding a modified single chain IL-12 (i.e., p40/p35 heterodimer), which is not secreted but tethered to the cell membrane (Fig. 6 of 2017/0291934, see also p. 93, 3rd & 6th para., p. 94, 2nd para., Table XA, p. 95, Fig. XB of 62/074,875 provisional application shown below with labeling).
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718
985
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Furthermore, in regard to claims 1 and 16, Reed teaches the non-secreted IL-12 has the domain order of p40-linker-p35 (Fig. 2 of 2017/0291934, see also Fig. 1 of 62/074,875 provisional application shown below).
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151
844
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Furthermore in regard to claim 1 (as well as claim 15), Reed teaches the non-secreted IL-12 does not contain a secretory signal peptide ([0153, 0155, 0176, 0178] of 2017/0291934, see p. 38, 3rd para., p. 39, 2nd para., p. 44, 3rd para., p. 45, 2nd para. p. 84, last para., p. 85, 1st para. of 62/074,875 provisional application). For example, Reed explicitly states that the “p40 domain (p40N) may lack a signal sequence” (p. 38, 3rd para., line 2 of 62/074,875 provisional application, see also p. 44 3rd para. of ‘875 application). Similarly, Reed states “the IL-12 p35 domain (iii) encoded by polynucleotides for use in the invention is a mature IL-12 p35 subunit, lacking a signal peptide” (p. 39, 2nd para., lines 1-2 of 62/074,875 provisional application, see also p. 45, 2nd para. of ‘875 application). In fact, when enumerating the p40/p35 vector constructs of Table 1:Human scIL-12 constructs, Reed states that the IL-12 constructs “may not comprise, a signal peptide sequence” (p. 84, last para., see also p. 85, 1st para. of 62/074,875 provisional application). Furthermore, Reed explicitly discloses a p35(35-253) subunit and p40(23-328) subunit as part of the scIL-12 constructs (p. 84, Table 1, last two rows of 62/074,875 provisional application).
Furthermore in regard to claims 1 and 16 and the claimed p40 nucleotide sequence of SEQ ID NO: 4, Reed teaches the human p40 subunit of IL-12 is encoded by SEQ ID NO: 1 (p. 37, last para. of 62/074,875 provisional application), which is 100% identical to instantly claimed SEQ ID NO: 4, with the exceptions of nucleotides 1-3 corresponding to the start codon (ATG) of SEQ ID NO: 4, and the absence of the first 22 amino acid signal sequence (i.e., nucleotides 1-66 of SEQ ID NO: 1) that is defined by Reed as missing in the p40(23-328) subunit (see also p. 40, last para. of 62/074,875 provisional application, see alignment below):
SEQ 1 67 ATATGGGAACTGAAGAAAGATGTTTATGTCGTAGAATTGGATTGGTATCCGGATGCCCCT 126
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
SEQ 4 4 ATATGGGAACTGAAGAAAGATGTTTATGTCGTAGAATTGGATTGGTATCCGGATGCCCCT 63
SEQ 1 127 GGAGAAATGGTGGTCCTCACCTGTGACACCCCTGAAGAAGATGGTATCACCTGGACCTTG 186
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
SEQ 4 64 GGAGAAATGGTGGTCCTCACCTGTGACACCCCTGAAGAAGATGGTATCACCTGGACCTTG 123
SEQ 1 187 GACCAGAGCAGTGAGGTCTTAGGCTCTGGCAAAACCCTGACCATCCAAGTCAAAGAGTTT 246
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
SEQ 4 124 GACCAGAGCAGTGAGGTCTTAGGCTCTGGCAAAACCCTGACCATCCAAGTCAAAGAGTTT 183
SEQ 1 247 GGAGATGCTGGCCAGTACACCTGTCACAAAGGAGGCGAGGTTCTAAGCCATTCGCTCCTG 306
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
SEQ 4 184 GGAGATGCTGGCCAGTACACCTGTCACAAAGGAGGCGAGGTTCTAAGCCATTCGCTCCTG 243
SEQ 1 307 CTGCTTCACAAAAAGGAAGATGGAATTTGGTCCACTGATATTTTAAAGGACCAGAAAGAA 366
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
SEQ 4 244 CTGCTTCACAAAAAGGAAGATGGAATTTGGTCCACTGATATTTTAAAGGACCAGAAAGAA 303
SEQ 1 367 CCCAAAAATAAGACCTTTCTAAGATGCGAGGCCAAGAATTATTCTGGACGTTTCACCTGC 426
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
SEQ 4 304 CCCAAAAATAAGACCTTTCTAAGATGCGAGGCCAAGAATTATTCTGGACGTTTCACCTGC 363
SEQ 1 427 TGGTGGCTGACGACAATCAGTACTGATTTGACATTCAGTGTCAAAAGCAGCAGAGGCTCT 486
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
SEQ 4 364 TGGTGGCTGACGACAATCAGTACTGATTTGACATTCAGTGTCAAAAGCAGCAGAGGCTCT 423
SEQ 1 487 TCTGACCCCCAAGGGGTGACGTGCGGAGCTGCTACACTCTCTGCAGAGAGAGTCAGAGGG 546
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
SEQ 4 424 TCTGACCCCCAAGGGGTGACGTGCGGAGCTGCTACACTCTCTGCAGAGAGAGTCAGAGGG 483
SEQ 1 547 GACAACAAGGAGTATGAGTACTCAGTGGAGTGCCAGGAGGACAGTGCCTGCCCAGCTGCT 606
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
SEQ 4 484 GACAACAAGGAGTATGAGTACTCAGTGGAGTGCCAGGAGGACAGTGCCTGCCCAGCTGCT 543
SEQ 1 607 GAGGAGAGTCTGCCCATTGAGGTCATGGTGGATGCCGTTCACAAGCTCAAGTATGAAAAC 666
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
SEQ 4 544 GAGGAGAGTCTGCCCATTGAGGTCATGGTGGATGCCGTTCACAAGCTCAAGTATGAAAAC 603
SEQ 1 667 TACACCAGCAGCTTCTTCATCAGGGACATCATCAAACCTGACCCACCCAAGAACTTGCAG 726
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
SEQ 4 604 TACACCAGCAGCTTCTTCATCAGGGACATCATCAAACCTGACCCACCCAAGAACTTGCAG 663
SEQ 1 727 CTGAAGCCATTAAAGAATTCTCGGCAGGTGGAGGTCAGCTGGGAGTACCCTGACACCTGG 786
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
SEQ 4 664 CTGAAGCCATTAAAGAATTCTCGGCAGGTGGAGGTCAGCTGGGAGTACCCTGACACCTGG 723
SEQ 1 787 AGTACTCCACATTCCTACTTCTCCCTGACATTCTGCGTTCAGGTCCAGGGCAAGAGCAAG 846
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
SEQ 4 724 AGTACTCCACATTCCTACTTCTCCCTGACATTCTGCGTTCAGGTCCAGGGCAAGAGCAAG 783
SEQ 1 847 AGAGAAAAGAAAGATAGAGTCTTCACGGACAAGACCTCAGCCACGGTCATCTGCCGCAAA 906
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
SEQ 4 784 AGAGAAAAGAAAGATAGAGTCTTCACGGACAAGACCTCAGCCACGGTCATCTGCCGCAAA 843
SEQ 1 907 AATGCCAGCATTAGCGTGCGGGCCCAGGACCGCTACTATAGCTCATCTTGGAGCGAATGG 966
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
SEQ 4 844 AATGCCAGCATTAGCGTGCGGGCCCAGGACCGCTACTATAGCTCATCTTGGAGCGAATGG 903
SEQ 1 967 GCATCTGTGCCCTGCAGT 984
||||||||||||||||||
SEQ 4 904 GCATCTGTGCCCTGCAGT 921
In regard to including the missing ATG corresponding to the start methionine at position 1 in the p40 subunit as taught by Reed, as stated supra, Reed teaches the non-secreted IL-12 has the domain order of a p40-linker-p35 ([0058] and Fig. 2 of 2017/0291934, see also p. 10, last para., and Fig. 1 of 62/074,875 provisional); therefore, it would have been obvious to one of ordinary skill to include an ATG with N-terminal p40 subunit in the p40-linker-p35 scIL12 vector of Reed with a reasonable expectation of success. Thus, Reed reasonably suggests a non-secretory human p40 subunit that is missing is secretion signal sequence but includes a start ATG consisting of the nucleotide sequence of SEQ ID NO: 4.
Finally in regard to claims 1 and 16, Reed teaches the scIL-12 is in an adenoviral vector to be administering to a subject to treat cancers (p. 20, 2nd para., p. 21, 1st para., p. 27, 1st para., p. 57, 2nd para., p. 58, 2nd para., p. 59, 5th para. p. 61, 2nd para., p. 73, 1st para., p74, 4th para., p. 76, 3rd para., p. 93, 4th & 5th para. of 62/074,875 provisional application).
However in regard to claims 1 and 16, although Reed et al. teaches the vector is an adenoviral vector, they are silent with respect to an oncolytic adenoviral vector.
[AltContent: textbox ([img-media_image3.png])]Poutou teaches methods for treating cancers in a subject and reducing the toxicity of IL-12 gene therapy comprising an oncolytic adenoviral type 5 vector (OAV) comprising membrane anchored p40/p35 scIL-12 constructs (Abstract, p. 704, Materials & Methods, see Fig 1 adjacent, especially “OAV-scIL12-TM”). Specifically, Poutou teaches the fusion with the TM was prevented secretion (p.697, Results, col 2, 1st para.).
Accordingly, it would have been obvious to one of ordinary skill in the art at the time of filing to practice a method of treating cancer comprising administering to a subject an adenoviral vector comprising a nucleotide encoding the membrane anchored scIL-12 with no signal sequence comprising the p40 subunit consisting of SEQ ID NO: 4 as suggested by Reed and choose an oncolytic adenovirus type 5 vector as taught by Poutou with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do as taught by Poutou because the membrane anchoring of the IL-12 obtains a high local concentration at the tumor site without extensive release into the circulation, and when incorporated into the oncolytic adenoviral type 5 vector, a potent antitumor effect can be achieved with negligible elevations of IL-12 in the serum, thereby increasing the safety and tolerance of OAVs (Introduction, p. 697, 1st para.).
In regard to claims 2 and 3, as stated supra, Reed teaches the subject has cancer and specifically suggests pancreatic cancer (p. 72, 3rd para. of 62/074,875 provisional application). Furthermore, Poutou teaches that the OVA-scIL12 could effectively kill pancreatic tumor cells in a subject (see Figs 5 & 6), thereby establishing that a method for treating pancreatic cancer according to Reed et al. could have been conducted with a reasonable expectation of success.
In regard to claims 8 and 9, as stated supra, Reed teaches p40(23-328) subunit as part of the single chain IL-12 as derived from the human p40 subunit of SEQ ID NO: 2 (p. 40, last para. of 62/074,875 provisional application). Again, it would have been obvious to add a start methionine and remove the 22 amino acid signal sequence as defined by Reed (see p. 40, last para. of 62/074,875 provisional application), as such SEQ ID NO: 2 of Reed and the first 307 amino acids from SEQ ID NO:2 of claim 8 are identical (see alignment below of Claim 8 SEQ2 vs. SEQ2 of Reed). The next 10 amino acids of SEQ ID NO:2 of claim 8 is the VPGVGVPGVG linker. Finally, Reed teaches the p35(35-253) subunit of IL-12 is derived from SEQ ID NO: 4 (p. 50, last para. of 62/074,875 provisional application). Note that SEQ ID NO: 2 of claim 8 and SEQ ID NO:4 of Reed are identical (see alignment below of Claim 8 SEQ2 vs. SEQ4 of Reed) with the exception that the p35(35-253) subunit of Reed comprises an extra 21 amino acids. Thus, Reed makes obvious a variant (i.e., different linker and slightly longer p35 subunit) of a fusion protein of SEQ ID NO: 2 of claim 8. In regard to claim 9, as stated supra, the only difference between the two sequences is the 10 amino acid linker, and an extra 21 amino acids in the p35(35-253) subunit; thus 484/515 amino acids are identical (i.e., about 94% sequence identity).
10 20 30 40 50 60
SEQ2 IWELKKDVYVVELDWYPDAPGEMVVLTCDTPEEDGITWTLDQSSEVLGSGKTLTIQVKEF
::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::
SEQ2 IWELKKDVYVVELDWYPDAPGEMVVLTCDTPEEDGITWTLDQSSEVLGSGKTLTIQVKEF
30 40 50 60 70 80
70 80 90 100 110 120
SEQ2 GDAGQYTCHKGGEVLSHSLLLLHKKEDGIWSTDILKDQKEPKNKTFLRCEAKNYSGRFTC
::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::
SEQ2 GDAGQYTCHKGGEVLSHSLLLLHKKEDGIWSTDILKDQKEPKNKTFLRCEAKNYSGRFTC
90 100 110 120 130 140
130 140 150 160 170 180
SEQ2 WWLTTISTDLTFSVKSSRGSSDPQGVTCGAATLSAERVRGDNKEYEYSVECQEDSACPAA
::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::
SEQ2 WWLTTISTDLTFSVKSSRGSSDPQGVTCGAATLSAERVRGDNKEYEYSVECQEDSACPAA
150 160 170 180 190 200
190 200 210 220 230 240
SEQ2 EESLPIEVMVDAVHKLKYENYTSSFFIRDIIKPDPPKNLQLKPLKNSRQVEVSWEYPDTW
::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::
SEQ2 EESLPIEVMVDAVHKLKYENYTSSFFIRDIIKPDPPKNLQLKPLKNSRQVEVSWEYPDTW
210 220 230 240 250 260
250 260 270 280 290 300
SEQ2 STPHSYFSLTFCVQVQGKSKREKKDRVFTDKTSATVICRKNASISVRAQDRYYSSSWSEW
::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::
SEQ2 STPHSYFSLTFCVQVQGKSKREKKDRVFTDKTSATVICRKNASISVRAQDRYYSSSWSEW
270 280 290 300 310 320
320 330 340 350 360
SEQ2 ASVPCSVPGVGVPGVGARNLPVATPDPGMFPCLHHSQNLLRAVSNMLQKARQTLEFYPCT
:::::: (LINKER) ::::::::::::::::::::::::::::::::::::::::::::
SEQ2 ASVPCS SEQ4 ARNLPVATPDPGMFPCLHHSQNLLRAVSNMLQKARQTLEFYPCT
60 70 80 90 100
370 380 390 400 410 420
SEQ2 SEEIDHEDITKDKTSTVEACLPLELTKNESCLNSRETSFITNGSCLASRKTSFMMALCLS
::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::
SEQ4 SEEIDHEDITKDKTSTVEACLPLELTKNESCLNSRETSFITNGSCLASRKTSFMMALCLS
110 120 130 140 150 160
430 440 450 460 470 480
SEQ2 SIYEDLKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVIDELMQALNFNSETVPQKSSLEE
::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::
SEQ4 SIYEDLKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVIDELMQALNFNSETVPQKSSLEE
170 180 190 200 210 220
490 500 510
SEQ2 PDFYKTKIKLCILLHAFRIRAVTIDRVMSYLNAS
::::::::::::::::::::::::::::::::::
SEQ4 PDFYKTKIKLCILLHAFRIRAVTIDRVMSYLNAS
230 240 250
In regard to claim 11, as stated above, Reed teaches the nucleic acid for human p40 subunit (see SEQ ID NO: 1 of Reed) and the nucleic acid for the human p35 subunit (see SEQ ID NO: 3 of Reed p. 39, 2nd para. of 62/074,875 provisional application), which are identical to the nucleic acid sequences found in SEQ ID NO: 1 of claim 11 (with the exception of the linker and the longer p35 subunit). Thus, the nucleic acid of Reed comprises sequences capable of hybridizing to SEQ ID NO:1 under stringent conditions. Furthermore in regard to claim 18, as stated supra, Reed teaches the nucleic acid encoding the scIL-12 is inserted into an adenoviral vector.
In regard to claim 12, as stated supra, Poutou makes obvious the adenovirus type 5 vector (OAV) for the treatment of cancer with the membraned anchored scIL-12.
In regard to claim 14, as stated supra, Reed teaches the p35(35-253) subunit of IL-12 is derived from SEQ ID NO: 4, which comprises an amino acid sequence that is 100% identical to the 198 amino acid sequence of SEQ ID NO: 5.
In regard to claim 15, as stated supra, Reed teaches neither the p35(35-253) subunit nor p40(23-328) subunit comprise a full signal peptide.
In regard to claim 17, Reed teaches the non-secreted IL-12 vector is in a pharmaceutical composition (p. 5, 6th para., p. 59, 3rd para. of 62/074,875 provisional application), and is a medicine for treating infections and tumors.
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
RESPONSE TO ARGUMENTS
Applicant's arguments and the Wang declaration filed 3/18/2026 are acknowledged and have been addressed above.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Reed et al., (US2017/0291934, filed 9/21/2015, with priority to provisional applications 62/053,628, filed 9/22/2014, and 62/074,875, filed 11/04/2014, see IDS filed 6/02/2022), in view of Tang et al., (US2009/0142855, filed 6/30/2006, see IDS filed 6/02/2022).
As discussed previously, Reed et al. suggest a method of treatment comprising OAV comprising the nucleotide sequence encoding an membrane anchored scIL-12 (i.e., p40-linker-p35 heterodimer) that does not contain a secretory signal peptide, where the p40 subunit consists of SEQ ID NO: 4.
However, although Reed teaches the linker is 10 amino acids in length (p. 39, 1st para. of 62/074,875 provisional application), they are silent with respect to the linker of SEQ ID NO: 7.
Tang teaches compositions of peptides of the IL-12 family of cytokines. With respect to claim 7, Tang teaches the linker of VPGVGVPGVG (SEQ ID NO: 8) [0014-0015, 0043], which is identical to SEQ ID NO: 7 of claim 7.
Accordingly, it would have been obvious to one of ordinary skill in the art at the time of filing to prepare the recombinant vector comprising the nucleotide sequence encoding a modified IL-12, which is not secreted as taught by Reed and substitute the linker of Tang with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so as taught by Tang because the taught linker is an elastin motif that recapitulates the proper folding of the IL-12 p40/p35 heterodimer (p. 7, Example 4, Table 3).
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
RESPONSE TO ARGUMENTS
Applicant's arguments and the Wang declaration filed 3/18/2026 are acknowledged and have been addressed 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 obviousness-type double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); 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 conflicting 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.
Effective January 1, 1994, a registered attorney or agent of record may sign a terminal disclaimer. A terminal disclaimer signed by the assignee must fully comply with 37 CFR 3.73(b).
Claims 1-3, 7-9, 11-12, 14-17 are rejected on the grounds of nonstatutory double patenting over claim 1-5 of U.S. Patent No. 11,345,732 (Wang et al., Patented 5/31/2022).
The subject matter claimed in the instant application is fully disclosed in the referenced patent as follows: the method for treating cancer and oncolytic adenoviral vector Ad-TD-nsIL12 known by CCTCC NO: V201520 of cited patent anticipates the method and OAV of instant application. It is clear that all the elements of the cited patent claims are to be found in instant claims. The difference between the cited patent claims and the instant claims lies in the fact that the cited patent claims are much more specific with respect to the biological deposit. Thus the invention of said claims of the cited patent are in effect “species” of the “generic” invention of the instant claim. It has been held that the generic invention is “anticipated” by the “species”. See In re Goodman, 29 USPQ2d 2010 (Fed. Cir. 1993).
Since the instant application claims are anticipated by cited patent claims, said claims are not patentably distinct.
RESPONSE TO ARGUMENTS
Applicant's remarks filed 3/18/2016 indicate a terminal disclaimer will be filed upon the indication of allowable subject matter.
Conclusion
No claims are allowed.
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/ARTHUR S LEONARD/Examiner, Art Unit 1631
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