DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
The amendments and remarks filed 2/27/26 are acknowledged. Claim 68 has been amended. Claims 1-67 and 69-70 have been canceled. Claims 68 and 71-84 are pending.
Claims 83-84 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 9/19/25.
Claims 68 and 71-82 are under examination.
New Rejections Necessitated by Applicant’s Amendment
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.
Claims 68 and 71-82 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The instant claims are drawn to a composition for increasing an immune response that comprises a) a nucleic acid sequence that encodes a functional fragment of IL-12 p35 subunit and b) a nucleic acid sequence that encodes a functional fragment of IL-12 p40 subunit, wherein the nucleic acid sequence that encodes a functional fragment of IL-12 p35 subunit is at least 80% homologous to SEQ ID NO:1 and encodes a protein at least 80% homologous to SEQ ID NO:2, and the nucleic acid sequence that encodes a functional fragment of IL-12 p40 subunit is at least 80% homologous to SEQ ID NO:3 and encodes a protein at least 80% homologous to SEQ ID NO:4.
The specification teaches an isolated nucleic acid comprising the nucleotide sequence set forth in SEQ ID NO: 1 that encodes the IL-12p35 of SEQ ID NO:2; and an isolated nucleic acid comprising the nucleotide sequence set forth in SEQ ID NO: 3 that encodes the IL-12p40 of SEQ IDNO:4.
Although the claims are inclusive of the nucleic acid comprising the nucleotide sequence set forth in SEQ ID NO: 1 that encodes the IL-12p35 of SEQ ID NO:2; and an isolated nucleic acid comprising the nucleotide sequence set forth in SEQ ID NO: 3 that encodes the IL-12p40 of SEQ IDNO:4, the claims broadly encompass functional fragments of the IL-12p35 subunit that share 85% homology to SEQ ID NO: 1 and encodes a protein at least 85% homologous to SEQ ID NO: 2, and functional fragments of IL-12p40 that is at least 85% homologous to SEQ ID NO: 3 and encodes a protein at least 85% homologous to SEQ ID NO: 4. comprising the nucleotide sequence set forth in SEQ ID NO: 1 that encodes the IL-12p35 of SEQ ID NO:2; and an isolated nucleic acid comprising the nucleotide sequence set forth in SEQ ID NO: 3 that encodes the IL-12p40 of SEQ ID NO:4. This would represent a large pool of variant polypeptides that must have similar functional activity (i.e., increase an immune response). A variance of 15%, for example, in the amino acid sequence set forth in SEQ ID NO: 2 that is 219 nucleotides in length translates into 32 amino acid residues that may be added, deleted, substituted, or otherwise mutated anywhere throughout the entire length of the 219 amino acid sequence. There is no limit in the claims, as written, that the variance be contiguous. Moreover, there is no limitation stating that the substitution, for example, be a conservative substitution. As a result, there are potentially thousands of variant permutations that could be made and still maintain a variance of 85%. Applicants have not described which domain or portions of SEQ ID NOs: 1-4 that are critical to the function of the protein. The specification provides limited guidance regarding which amino acids can be modified in the genus of polypeptides, while maintaining any given function. Therefore, these structures (i.e., sequence variants) are claimed only be their functional characteristics and the specification fails to provide sufficient correlation between the claimed functional characteristics and the necessary structural components (i.e., critical domains within the sequences).
Furthermore, Applicants have not shown possession of a representative number of species that have the claimed function(s). While the specification clearly sets forth a correlation between the fully disclosed isolated nucleic acid comprising the nucleotide sequence set forth in SEQ ID NO: 1 that encodes the IL-12p35 of SEQ ID NO:2; and an isolated nucleic acid comprising the nucleotide sequence set forth in SEQ ID NO: 3 that encodes the IL-12p40 of SEQ IDNO:4, and the claimed function of increasing an immune response, this correlation does not appear to be clearly present in the breadth of the claims. As noted above, the claims are not limited to the disclosed nucleic and amino acid sequences and encompass variants having 85% homology to the claimed sequences. Thus, the genus has substantial variation because of the numerous alternatives and combinations permitted. There is no description of the structure common to the members of the genus such that one of skill in the art can visualize or recognize the members of the genus. Therefore, only a few species have been described and this is not considered to be representative of the breadth of the genus.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
With the exception of the isolated nucleic acid comprising the nucleotide sequence set forth in SEQ ID NO: 1 that encodes the IL-12p35 of SEQ ID NO:2; and an isolated nucleic acid comprising the nucleotide sequence set forth in SEQ ID NO: 3 that encodes the IL-12p40 of SEQ IDNO:4, the skilled artisan cannot envision the detailed chemical structure of the encompassed agents, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The nucleic acid and/or protein itself is required. See Fiers v. Revel, 25 USPQ2d 1601,1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481,1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that: ...To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc., 107 F.3d 1565, 1572, 41 USPQ2dl961,1966 (1997); In re Gosteli, 872 F.2dl008,1012,10 USPQ2dl614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d 1966.
Protein chemistry is probably one of the most unpredictable areas of biotechnology. Consequently, the effects of sequence dissimilarities upon protein structure and function cannot be predicted. Punta et al. (PLoS Comput Biol 4(10): e1000160, 2008) teach that homology (both orthology and paralogy) does not guarantee conservation of function (See page 2). Punta et al. teach that relatively small difference in sequence can sometimes cause quite radical changes in functional properties, such as a change of enzymatic action, or even loss or acquisition of enzymatic activity itself (See page 2). Punta et al. teach that it is also apparent that there is no sequence similarity threshold that guarantees that two proteins share the same function (see page 2). Punta et al. teach that homology between two proteins does not guarantee that they have the same function, not even when sequence similarity is very high (including 100% sequence identity) (See page 2 and table 2). Punta et al. teach that proteins live and function in 3D, and therefore structural information is very helpful for predicating function (See page 4). However, as with sequence, two proteins having the same overall architecture, and even conserved functional residues, can have unrelated functions (See page 4). Punta et al. teach that still; structural knowledge is an extremely powerful tool for computational function prediction (See page 5).
Similarly, Whisstock et al. (Quarterly Reviews in Biophysics. 36(3):307-340, 2007) teach that the prediction of protein function from sequence and structure is a difficult problem (See abstract). Although many families of proteins contain homologues with the same function, homologous proteins often have different functions as the sequences progressively diverge (See page 309). Whisstock et al. teach that moreover, even closely related proteins can change function, either through divergence to a related function or by recruitment for a very different function (See page 309). Further, Whisstock et al. note that in some instances, even sequences that are the same can have different functions. For example, eye lens proteins in the suck are identical in sequence to active lactate dehydrogenase and enolase in other tissues, although they do not encounter the substrates in the eye (See page 310). Whisstock et al. teach that assigning a function to an amino acid sequence based upon similarity becomes significantly more complex as the similarity between the sequence and a putative homologue fall (See page 321). Whisstock et al. teach that while it is hopeful that similar proteins will share similar functions, substitution of a single, critically placed amino acid in an active-site may be sufficient to alter a protein’s role fundamentally (See pages 321-323).
The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J. Cell Biol. 111:2129-2138, 1990) who teach that replacement of a single lysine reside at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Song et al. (Molecular Biology of the Cell, 15:1287–1296, March 2004) who teach that substitution of alanine for aspartate in survivin results in the conversion of survivins’ apoptotic function from anti-apoptotic to proapoptotic and changes in its subcellular localization (See page 1287-1289). Moreover, Defeo-Jones et al. (Molecular and Cellular Biology, Sept. 1989, p. 4083-4086) teach that the conservative substitution of lysine for arginine at position 42 completely eliminated biological activity (See abstract and pages 4084-4085). These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Additionally, Bork (Genome Research, 2000; 10:398-400) clearly teaches the pitfalls associated with comparative sequence analysis for predicting protein function because of the known error margins for high-throughput computational methods. Bork specifically teaches that computational sequence analysis is far from perfect, despite the fact that sequencing itself is highly automated and accurate (p. 398, column 1). One of the reasons for the inaccuracy is that the quality of data in public sequence databases is still insufficient. This is particularly true for data on protein function. Protein function is context dependent, and both molecular and cellular aspects have to be considered (p. 398, column 2). Conclusions from the comparison analysis are often stretched with regard to protein products (p. 398, column 3). Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable (p. 399, column 2). Most features predicted with an accuracy of greater than 70% are of structural nature and, at best, only indirectly imply a certain functionality (see legend for table 1, page 399). As more sequences are added and as errors accumulate and propagate it becomes more difficult to infer correct function from the many possibilities revealed by database search (p. 399, paragraph bridging columns 2 and 3). The reference finally cautions that although the current methods seem to capture important features and explain general trends, 30% of those features are missing or predicted wrongly. This has to be kept in mind when processing the results further (p. 400, paragraph bridging cols 1 and 2).
Given not only the teachings of Punta et al., Whisstock et al., Song et al., Burgess et al., and Defeo-Jones et al., but also the limitations and pitfalls of using computational sequence analysis and the unknown effects of alternative splicing, post translational modification and cellular context on protein function as taught by Bork, the claimed proteins having the required function(s) could not be predicted based on sequence identity. Clearly, it could not be predicted that a polypeptide or a variant that shares only partial homology with a disclosed protein or that is a fragment of a protein will function in a given manner. Therefore, the state of the art supports that even the skilled artisan requires guidance on the critical structures of the nucleic acid and amino acid sequences per se and thereby does not provide adequate written description support for which structural features of any given polypeptide would predictably retain their functional activities.
Applicant is reminded that generally, in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus (Enzo Biochem, Inc. v. Gen- Probe Inc., 323 F.3d 956 (Fed. Cir. 2002); Noelle v. Lederman, 355 F.3d 1343 (Fed. Cir. 2004); Regents of the University of California v. Eli Lilly Co., 119 F.3d 1559 (Fed. Cir. 1997)). A patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017) at page 1358). An adequate written description must contain enough information about the actual makeup of the claimed products — “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361).
Adequate written description requires more than a mere statement that is part of the invention. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chungai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
The University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that: ...To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention.” Lockwood v. American Airlines Inc. 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus an Applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2dat1966.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, ‘does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the “written description" requirement is broader than to merely explain how to "make and use"; the Applicant must convey with reasonable clarity to those skilled in the art, that as of the filing date sought, he or she was in possession of the invention. The invention is for purposes of the “written description” inquiry, whatever is now claimed. See Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).
Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed. Therefore, for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
Applicant’s Arguments
Applicants argues that the claims have been amended to recite "[a] composition for increasing an immune response that comprises a) a nucleic acid sequence that encodes IL-12 p35 subunit and b) a nucleic acid sequence that encodes IL-12 p40 subunit, wherein the nucleic acid sequence that encodes IL-12 p35 subunit is at least 85% identical to SEQ ID NO:1 and encodes a protein at least 85% identical to SEQ ID NO:2, and the nucleic acid sequence that encodes IL-12 p40 subunit is at least 85% identical to SEQ ID NO:3 and encodes a protein at least 85% identical to SEQ ID NO:4."
Applicants argues that the Specification as-filed provides written description for the instant claims because the Specification teaches the specific nucleic acid sequences that encode IL-12 p35 or IL-12 p40 subunits recited in the instant claims, as well as the specific nucleic acid sequences that encode IL-12 p35 or IL-12 p40 subunits or fragments thereof recited in claim 85. Applicants argues that the ordinarily skilled artisan would be able to readily envision the structure and function of the presently encompassed nucleic acid and amino acid sequences. Applicant argues that the optimized sequences are provided in the claims and the disclosure. Applicant argues that the Specification as-filed also discloses that sequences with less than 100% homology to original sequences are part of the present invention and may be readily produced and utilized by ordinary means available to the skilled artisan (e.g., pages 15 and 17-19 of the Specification as-filed).
Applicants argues that the function (i.e., increasing an immune response) of recited sequences is clearly set forth in the Specification as-filed (e.g., Examples 1-3, Figures 1-3, and pages 35 and 36 of the Specification as-filed) and the instant claims. Applicant argues that the structure/function analyses of IL-12 p35 and IL-12 p40 known in the art makes it clear that the Specification provides ample written description support for different nucleic acid sequences that encode IL-12 p35 and IL-12 p40.
Response to Arguments
Applicant’s arguments have been full considered but they are not persuasive. With regards to Applicant’s argument that the amended claims are fully supported by the specification, the Office disagrees and notes a careful review of the specification does not provide adequate support for the sequence variants having at least 85% sequence identity to SEQ ID NOs: 1-4. Thus, this argument is not persuasive because it remains the Office’s position that these variants have not been described with sufficient particularity, such that one skilled in the art would recognize that Applicant had possession of the claimed invention, at the time of filing, because of (A) a lack of a correlation, known or disclosed, between the claimed functional requirements and the structures that meet those requirements; and/or (B) a lack of a representative number and variety of species to constitute possession of the full scope of the claimed genus.
The instant specification provides complete structural information for the species HuIL12-opt and teaches HuIL12-opt sequences are optimized sequences that encode human IL-12 subunits. The HuILl12-opt sequence that is the coding sequence that encodes human IL-12 p35 subunit is disclosed in SEQ ID NO:1. The HuIL12-opt sequence that is the 219 amino acid IL- 12 p35 subunit amino acid sequence encoded thereby is disclosed as SEQ ID NO.2. The HuIL 12-opt sequence that is the coding sequence that encodes human IL-12 p40
subunit is disclosed as SEQ ID NO:3. The HuIL12-opt sequence that is the 328 amino acid IL- 12 p40 subunit amino acid sequence encoded thereby is disclosed as SEQ ID NO.4.
However, no fragments or variants of these sequences are disclosed that have the claimed function. The claims cover a broad genus of sequence variants that can differ from SEQ ID NOs: 1-4 by 15% identity, and must retain their functional activity. The specification provides no guidance regarding which 15% of the sequences can be altered while maintaining any given function. Therefore, these sequence variants have no correlation between their structure and function.
Further, as noted in the rejection above, the specification does not provide a representative number of species. MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus (see, e.g., MPEP § 2163(II)(3)(a), MPEP §2163.03(V)). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. In this case, the claims encompass an essentially infinite number of variants, but only one reduced to practice. In the absence of a reduction to practice of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. The specification only discloses working examples for a single species, but the claims cover a broad genus of sequence variants that can differ from SEQ ID NOs: 1-5 by 15% identity. Therefore, there is no disclosure of any other additional variants demonstrating that Applicant was in possession of the full scope of the invention.
Although the level of skill in the art is high, the predictability in the art is low due to the lack of detail regarding critical structural domains and motifs that would apply to variants within the broad scope of the claims. Specifically, an artisan would not be able to predict or identify, a priori, and in the absence of any guidance or consensus structures, exactly what variants with up to a 15% sequence difference to SEQ ID NO: 1-4 would be suitable for the invention and retain functional activity. Accordingly, in the absence of sufficient written description to demonstrate that the inventor was in possession of the claimed genus, including details about residues critical to the function of the protein suitable to the invention, an artisan would not reasonably conclude that Applicant possessed the full scope of the broad and highly varied claim scope. Consequently, based on the lack of information within the specification, there is evidence that a representative number and a representative variety of the numerous sequence variants with both the claimed structural attributes and functional properties have not yet been identified. MPEP 2163 which states an adequate written description of a chemical invention requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed; see, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004).
Claims 68 and 71-82 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 composition for increasing an immune response that comprises a) a nucleic acid sequence that encodes a functional fragment of IL-12 p35 subunit and b) a nucleic acid sequence that encodes a functional fragment of IL-12 p40 subunit, wherein the nucleic acid sequence that encodes the IL-12 p35 subunit is the nucleic acid sequence of SEQ ID NO:1 and encodes the protein set forth in SEQ ID NO:2, and the nucleic acid sequence that encodes a the IL-12 p40 subunit is the nucleic acid sequence set forth in SEQ ID NO:3 and encodes the protein set forth in SEQ ID NO:4, does not reasonably provide enablement for functional fragments having at least 85% homology to the recited sequences. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue include, but are not limited to: 1) nature of the invention, 2) state of the prior art, 3) relative skill of those in the art, 4) level of predictability, 5) existence of working samples, 6) breadth of claims, 7) amount of direction or guidance by the inventor, and 8) quantity of experimentation needed to make or use the invention. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
1) Nature of the invention and 6) Breadth of the claims
The nature of the invention is a composition for increasing an immune response that comprises a) a nucleic acid sequence that encodes a functional fragment of IL-12 p35 subunit and b) a nucleic acid sequence that encodes a functional fragment of IL-12 p40 subunit, wherein
the nucleic acid sequence that encodes a functional fragment of IL-12 p35 subunit is at least 85% homologous to SEQ ID NO:1 and encodes a protein at least 85% homologous to SEQ ID NO:2, and
the nucleic acid sequence that encodes a functional fragment of IL-12 p40 subunit is at least 85% homologous to SEQ ID NO:3 and encodes a protein at least 85% homologous to SEQ ID NO:4.
Therefore, the nature of the invention is a chemical case, wherein there is natural unpredictability in performance of certain species or sub-combinations other than those specifically enumerated; See MPEP 2163. Accordingly, it is the Office’s position that undue experimentation would be required to make and use the claimed functional fragments of IL-12 p35 subunit and IL-12 p40 subunit, with a reasonable expectation of success, because it would not be predictable from the disclosure of any particular species what other species may or may not work; See MPEP 2164.03.
Although the claims are inclusive of the nucleic acid comprising the nucleotide sequence set forth in SEQ ID NO: 1 that encodes the IL-12p35 of SEQ ID NO:2; and an isolated nucleic acid comprising the nucleotide sequence set forth in SEQ ID NO: 3 that encodes the IL-12p40 of SEQ IDNO:4, the claims broadly encompass functional fragments of the IL-12p35 subunit that share 85% homology to SEQ ID NO: 1 and encodes a protein at least 85% homologous to SEQ ID NO: 2, and functional fragments of IL-12p40 that is at least 85%homologous to SEQ ID NO: 3 and encodes a protein at least 85% homologous to SEQ ID NO: 4. comprising the nucleotide sequence set forth in SEQ ID NO: 1 that encodes the IL-12p35 of SEQ ID NO:2; and an isolated nucleic acid comprising the nucleotide sequence set forth in SEQ ID NO: 3 that encodes the IL-12p40 of SEQ ID NO:4. This would represent a large pool of variant polypeptides that must have similar functional activity. A variance of 15%, for example, in the amino acid sequence set forth in SEQ ID NO: 2 that is 219 nucleotides in length translates into 32 amino acid residues that may be added, deleted, substituted, or otherwise mutated anywhere throughout the entire length of the 219 amino acid sequence. There is no limit in the claims, as written, that the variance be contiguous. Moreover, there is no limitation stating that the substitution, for example, be a conservative substitution. As a result, there are potentially thousands of variant permutations that could be made and still maintain a variance of 85%. Applicants have not described which domain or portions of SEQ ID NOs: 1-4 that are critical to the function of the protein. The specification provides limited guidance regarding which amino acids can be modified in the genus of polypeptides, while maintaining any given function. Therefore, these structures (i.e., sequence variants) are claimed only be their functional characteristics and the specification fails to provide sufficient correlation between the claimed functional characteristics and the necessary structural components (i.e., critical domains within the sequences).
(5) The state of the prior art and (7) The predictability or unpredictability of the art
Protein chemistry is probably one of the most unpredictable areas of biotechnology. Consequently, the effects of sequence dissimilarities upon protein structure and function cannot be predicted. Punta et al. (PLoS Comput Biol 4(10): e1000160, 2008) teach that homology (both orthology and paralogy) does not guarantee conservation of function (See page 2). Punta et al. teach that relatively small difference in sequence can sometimes cause quite radical changes in functional properties, such as a change of enzymatic action, or even loss or acquisition of enzymatic activity itself (See page 2). Punta et al. teach that it is also apparent that there is no sequence similarity threshold that guarantees that two proteins share the same function (see page 2). Punta et al. teach that homology between two proteins does not guarantee that they have the same function, not even when sequence similarity is very high (including 100% sequence identity) (See page 2 and table 2). Punta et al. teach that proteins live and function in 3D, and therefore structural information is very helpful for predicating function (See page 4). However, as with sequence, two proteins having the same overall architecture, and even conserved functional residues, can have unrelated functions (See page 4). Punta et al. teach that still; structural knowledge is an extremely powerful tool for computational function prediction (See page 5).
Similarly, Whisstock et al. (Quarterly Reviews in Biophysics. 36(3):307-340, 2007) teach that the prediction of protein function from sequence and structure is a difficult problem (See abstract). Although many families of proteins contain homologues with the same function, homologous proteins often have different functions as the sequences progressively diverge (See page 309). Whisstock et al. teach that moreover, even closely related proteins can change function, either through divergence to a related function or by recruitment for a very different function (See page 309). Further, Whisstock et al. note that in some instances, even sequences that are the same can have different functions. For example, eye lens proteins in the suck are identical in sequence to active lactate dehydrogenase and enolase in other tissues, although they do not encounter the substrates in the eye (See page 310). Whisstock et al. teach that assigning a function to an amino acid sequence based upon similarity becomes significantly more complex as the similarity between the sequence and a putative homologue fall (See page 321). Whisstock et al. teach that while it is hopeful that similar proteins will share similar functions, substitution of a single, critically placed amino acid in an active-site may be sufficient to alter a protein’s role fundamentally (See pages 321-323).
The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J. Cell Biol. 111:2129-2138, 1990) who teach that replacement of a single lysine reside at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Song et al. (Molecular Biology of the Cell, 15:1287–1296, March 2004) who teach that substitution of alanine for aspartate in survivin results in the conversion of survivins’ apoptotic function from anti-apoptotic to proapoptotic and changes in its subcellular localization (See page 1287-1289). Moreover, Defeo-Jones et al. (Molecular and Cellular Biology, Sept. 1989, p. 4083-4086) teach that the conservative substitution of lysine for arginine at position 42 completely eliminated biological activity (See abstract and pages 4084-4085). These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Additionally, Bork (Genome Research, 2000; 10:398-400) clearly teaches the pitfalls associated with comparative sequence analysis for predicting protein function because of the known error margins for high-throughput computational methods. Bork specifically teaches that computational sequence analysis is far from perfect, despite the fact that sequencing itself is highly automated and accurate (p. 398, column 1). One of the reasons for the inaccuracy is that the quality of data in public sequence databases is still insufficient. This is particularly true for data on protein function. Protein function is context dependent, and both molecular and cellular aspects have to be considered (p. 398, column 2). Conclusions from the comparison analysis are often stretched with regard to protein products (p. 398, column 3). Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable (p. 399, column 2). Most features predicted with an accuracy of greater than 70% are of structural nature and, at best, only indirectly imply a certain functionality (see legend for table 1, page 399). As more sequences are added and as errors accumulate and propagate it becomes more difficult to infer correct function from the many possibilities revealed by database search (p. 399, paragraph bridging columns 2 and 3). The reference finally cautions that although the current methods seem to capture important features and explain general trends, 30% of those features are missing or predicted wrongly. This has to be kept in mind when processing the results further (p. 400, paragraph bridging cols 1 and 2).
Given not only the teachings of Punta et al., Whisstock et al., Song et al., Burgess et al., and Defeo-Jones et al., but also the limitations and pitfalls of using computational sequence analysis and the unknown effects of alternative splicing, post translational modification and cellular context on protein function as taught by Bork, the claimed proteins having the required function(s) could not be predicted based on sequence identity. Clearly, it could not be predicted that a polypeptide or a variant that shares only partial homology with a disclosed protein or that is a fragment of a protein will function in a given manner. Therefore, the state of the art supports that even the skilled artisan requires guidance on the critical structures of the nucleic acid and amino acid sequences per se and thereby does not provide adequate written description support for which structural features of any given polypeptide would predictably retain their functional activities.
(6) The amount of direction or guidance by the inventor; (7) The existence of working examples
The specification teaches an isolated nucleic acid comprising the nucleotide sequence set forth in SEQ ID NO: 1 that encodes the IL-12p35 of SEQ ID NO:2; and an isolated nucleic acid comprising the nucleotide sequence set forth in SEQ ID NO: 3 that encodes the IL-12p40 of SEQ IDNO:4.
Applying the above test to the facts of record, it is determined that 1) no declaration under 37 C.F.R. 1.132 or other relevant evidence has been made of record establishing the amount of experimentation necessary, 2) insufficient direction or guidance is presented in the specification with respect to making and using the claimed composition comprising functional fragments of the IL-12 p35 subunit and IL-12 p40 subunit, 3) the relative skill of those in the art is commonly recognized as quite high (post-doctoral level). One of skill in the art would require guidance, in order to make or use the claimed composition comprising functional fragments of the IL-12 p35 subunit and IL-12 p40 subunit. Without proper guidance, the experimentation to is undue.
The Applicant has not provided sufficient guidance to enable one of skill in the art to make and use the claimed invention in a manner reasonably correlated with the scope of the claims broadly including functional fragments of the IL-12 p35 subunit and IL-12 p40 subunit. The scope of the claims must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1970). Without such guidance, preventing heart transplantation and treating heart disease with the claimed functional fragments of the IL-12 p35 subunit and IL-12 p40 subunit is unpredictable and the experimentation left those skilled in the art is unnecessarily and improperly, extensive and undue. See Amgen Inc v Chugai Pharmaceutical Co Ltd. 927 F 2d 1200, 18 USPQ2d 1016 (Fed. Cir. 1991) at 18 USPQ2d 1026-1027 and Ex parte Forman, 230 U.S.P.Q. 546(Bd. Pat=. App & int. 1986).
In view of all of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention, and thus, the claimed invention does not satisfy the requirements of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph.
Applicant’s Arguments
Applicant argues that the claims have been amended to recites "[a] composition for increasing an immune response that comprises a) a nucleic acid sequence that encodes IL-12 p35 subunit and b) a nucleic acid sequence that encodes IL-12 p40 subunit, wherein the nucleic acid sequence that encodes IL-12 p35 subunit is at least 85% identical to SEQ ID NO:1 and encodes a protein at least 85% identical to SEQ ID NO:2, and the nucleic acid sequence that encodes IL-12 p40 subunit is at least 85% identical to SEQ ID NO:3 and encodes a protein at least 85% identical to SEQ ID NO:4."
Applicants argues that the Specification as-filed discloses that variants of polypeptides (e.g., less than 100% identity to the original polypeptide) differ in amino acid sequence by the insertion, deletion, or conservative substitution of amino acids, but retain at least one biological activity (e.g., page 16 of the Specification as-filed). Applicants respectfully argues that screening a large number of molecules for a function or activity is well within the purview of routine experimentation, and that, in the present case, the volume of the screen would be informed by both the teaching of the Specification as- filed and the knowledge imputed to the skilled artisan.
Applicants also respectfully submit that it is well-understood in the relevant art that substitutions of amino acids having similar hydrophilicity values can result in peptides retaining biological activity, for example immunogenicity (e.g., page 16 of the Specification as- filed). As such, this specific guidance, in combination with established assays for determining the ability of the compositions to increase an immune response and the finite length limits of the claimed fragments as recited in instant claims, greatly reduce the amount of experimentation necessary to perform the claimed invention across its entire breadth. Therefore, Applicants submit that the experimentation required to carry out the invention would not be undue.
Response to Arguments
Applicant’s arguments have been fully considered but they are not persuasive. Applicant’s amendment to limit the claims to a) a nucleic acid sequence that encodes IL-12 p35 subunit and b) a nucleic acid sequence that encodes IL-12 p40 subunit, wherein the nucleic acid sequence that encodes IL-12 p35 subunit is at least 85% identical to SEQ ID NO:1 and encodes a protein at least 85% identical to SEQ ID NO:2, and the nucleic acid sequence that encodes IL-12 p40 subunit is at least 85% identical to SEQ ID NO:3 and encodes a protein at least 85% identical to SEQ ID NO:4 is acknowledged. However, the claims still broadly encompass a vast genus of variants. To give an idea of the breadth of the claims, the sequence set forth in SEQ ID NO: 2 is 219 amino acids in length. Sequence variants that are at least 85% similar over the entire length, require 187 of the 219 to be maintained, leaving as little as 1, but up to 32, amino acids to be substituted (i.e. 187/219*100 = 85%; 219-187 = 32). As written, the claims allow for a substitution at any position along the 219 amino acid sequence to be modified while still meeting the structural limitation of at least 85% similar over the entire length of SEQ ID NO: 2. However, there are an almost unfathomable number of ways in which 1 to 32 amino acids (i.e. the sum of results for 1 change, 2 changes, 3 changes … 32 changes) can be selected from the 219 residues because, without any other limitations in the independent claim, each particular residue can be substituted with any one of the other 19 naturally occurring amino acids and still meet the limitation. For example, for just 1 change (i.e. only one amino acid substitution), there would be 218 unique sequences, but because the change at each residue can be substituted with any one of the other 19 naturally occurring amino acids, then the actual number of unique sequences encompassed is 4,142 (i.e. a sequence having an additional substitution at, for example, residue 33 with a cysteine, would be structurally distinct from a sequence having a substitution at residue 33 with a tryptophan; and 218 * 19 = 4,142). Yet, the claims allow for up to 32 unrestricted changes, anywhere along the length of SEQ ID NO:2, so with order of selection not important and repetition not allowed, the equation is X = 19 * [n!/(r!(n-r)!)], which for 32 changes, results in a number having more than 40 zeros (i.e. a trillion only has 12 zeros).
Furthermore, the art does not support the genus of variants. As noted in the rejection, it is not predictable that a particular substitution will maintain the function of a protein. For example, Burgess et al. (J. Cell Biol. 111:2129-2138, 1990) teach that replacement of a single lysine reside at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and Song et al. (Molecular Biology of the Cell, 15:1287–1296, March 2004) teach that substitution of alanine for aspartate in survivin results in the conversion of survivins’ apoptotic function from anti-apoptotic to proapoptotic and changes in its subcellular localization (See page 1287-1289). Moreover, Defeo-Jones et al. (Molecular and Cellular Biology, Sept. 1989, p. 4083-4086) teach that the conservative substitution of lysine for arginine at position 42 completely eliminated biological activity (See abstract and pages 4084-4085). These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
The specification discloses a single working example of a nucleic acid that falls within the scope of the claims. Given the lack of guidance provided by the specification, coupled with the lack of support provided by the art, and the unpredictability of determining which variants would have the claimed function of increasing an immune response, it would be undue experimentation for one of skill in the art to practice the claimed invention.
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 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); 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 nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined 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 § 2146 et seq. 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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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 www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 68 and 71-82 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 9,272,024. Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are drawn to a composition that comprises a) a nucleic acid sequence that encodes a functional fragment of IL-12 p35 subunit and b) a nucleic acid sequence that encodes a functional fragment of IL-12 p40 subunit, wherein the nucleic acid sequence that encodes a functional fragment of IL-12 p35 subunit is at least 85% homologous to SEQ ID NO:1 and encodes a protein at least 85% homologous to SEQ ID NO:2, and the nucleic acid sequence that encodes a functional fragment of IL-12 p40 subunit is at least 85% homologous to SEQ ID NO:3 and encodes a protein at least 85% homologous to SEQ ID NO:4.
The ‘024 claims teach a composition that comprises a) a nucleic acid sequence that encodes IL-12 p35 subunit and b) a nucleic acid sequence that encodes IL-12 p40 subunit, wherein the nucleic acid sequence that encodes IL-12 p35 subunit is at least 98% homologous to SEQ ID NO:1 and encodes a protein at least 98% homologous to SEQ ID NO:2, and the nucleic acid sequence that encodes IL-12 p40 subunit is at least 98% homologous to SEQ ID NO:3 and encodes a protein at least 98% homologous to SEQ ID NO:4. The ‘024 claims teach formulated for delivery to an individual using electroporation. The ‘024 claims teach wherein the nucleic acid sequence that encodes IL-12 p35 subunit is on a different nucleic acid molecule than the nucleic acid sequence that encodes IL-12 p40 subunit. The ‘024 claims teach wherein the nucleic acid sequence that encodes IL-12 p35 subunit is on a plasmid and the nucleic acid sequence that encodes IL-12 p40 subunit is on a different plasmid. The ‘024 claims teach wherein the nucleic acid sequence that encodes IL-12 p35 subunit and the nucleic acid sequence that encodes IL-12 p40 subunit are on the same nucleic acid molecule. The ‘024 claims teach wherein the nucleic acid sequence that encodes IL-12 p35 subunit and the nucleic acid sequence that encodes IL-12 p40 subunit are on the same plasmid. The ‘024 claims teach wherein the nucleic acid sequence that encodes IL-12 p35 subunit and the nucleic acid sequence that encodes IL-12 p40 subunit are on the same nucleic acid molecule and operably linked to different promoters. The ‘024 claims teach wherein the nucleic acid sequence that encodes IL-12 p35 subunit and the nucleic acid sequence that encodes IL-12 p40 subunit are on the same plasmid and operably linked to different promoters. The ‘024 claims teach further comprising a nucleic acid sequence that encodes an immunogen. The ‘024 claims teach further comprising a nucleic acid sequence that encodes an immunogen from a pathogen selected from the group consisting of: HIV, HPV, HCV, Influenza, Smallpox, Chikungunya, foot and mouth disease virus, Malaria, human cytomegalovirus, human respiratory syncytial virus, and MRSA. The ‘024 claims teach wherein the nucleic acid sequence that encodes IL-12 p35 subunit and the nucleic acid sequence that encodes IL-12 p40 subunit are incorporated into a viral particle. The ‘024 claims teach further comprising a nucleic acid sequence that encodes one or more proteins selected from the group consisting of: IL-15 and IL-28. Thus, the ‘024 claims anticipate the instant claims, and the ‘024 claims and instant claims are not patentably distinct.
Applicant’s Arguments
Applicant request that the rejection be held in abeyance until claims are deemed allowable in the instant application.
Response to Arguments
Applicant’s arguments have been fully considered but they are not persuasive. Applicant is reminded that a rejection under double patenting precludes the identification of allowable subject matter. MPEP 804 states that a complete response to a nonstatutory double patenting (NDP) rejection is either a reply by applicant showing that the claims subject to the rejection are patentably distinct from the reference claims or the filing of a terminal disclaimer in accordance with 37 CFR 1.321 in the pending application(s) with a reply to the Office action. Such a response is required even when the nonstatutory double patenting rejection is provisional. As filing a terminal disclaimer, or filing a showing that the claims subject to the rejection are patentably distinct from the reference application's claims, is necessary for further consideration of the rejection of the claims, such a filing should not be held in abeyance. Only objections or requirements as to form not necessary for further consideration of the claims may be held in abeyance until allowable subject matter is indicated. Therefore, an application must not be allowed unless the required compliant terminal disclaimer(s) is/are filed and/or the withdrawal of the nonstatutory double patenting rejection(s) is made of record by the examiner. Accordingly, the rejection is maintained.
Claims 68 and 71-82 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 9,981,036. Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are drawn to a composition that comprises a) a nucleic acid sequence that encodes a functional fragment of IL-12 p35 subunit and b) a nucleic acid sequence that encodes a functional fragment of IL-12 p40 subunit, wherein the nucleic acid sequence that encodes a functional fragment of IL-12 p35 subunit is at least 85% homologous to SEQ ID NO:1 and encodes a protein at least 85% homologous to SEQ ID NO:2, and the nucleic acid sequence that encodes a functional fragment of IL-12 p40 subunit is at least 85% homologous to SEQ ID NO:3 and encodes a protein at least 85% homologous to SEQ ID NO:4.
The ‘036 claims teach a composition for modulating an immune system that comprises a) a nucleic acid sequence that encodes an IL-12 p35 subunit and b) a nucleic acid sequence that encodes an IL-12 p40 subunit, wherein the nucleic acid sequence that encodes the IL-12 p35 subunit is at least 95% identical to SEQ ID NO:1 and encodes a protein at least 95% identical to SEQ ID NO:2, and the nucleic acid sequence that encodes the IL-12 p40 subunit is at least 95% identical to SEQ ID NO:3 and encodes a protein at least 95% identical to SEQ ID NO:4. The ‘036 claims teach comprising the nucleic acid sequence that encodes the IL-12 p35 subunit is at least 97% identical to SEQ ID NO:1 and encodes a protein at least 97% identical to SEQ ID NO:2, and the nucleic acid sequence that encodes the IL-12 p40 subunit is at least 97% identical to SEQ ID NO:3 and encodes a protein at least 97% identical to SEQ ID NO:4. The ‘036 claims teach formulated for delivery to an individual using electroporation. The ‘036 claims teach wherein the nucleic acid sequence that encodes IL-12 p35 subunit is on a different nucleic acid molecule than the nucleic acid sequence that encodes IL-12 p40 subunit. The ‘036 claims teach wherein the nucleic acid sequence that encodes IL-12 p35 subunit is on a plasmid and the nucleic acid sequence that encodes IL-12 p40 subunit is on a different plasmid. The ‘036 claims teach wherein the nucleic acid sequence that encodes IL-12 p35 subunit and the nucleic acid sequence that encodes IL-12 p40 subunit are on the same nucleic acid molecule. The ‘036 claims teach wherein the nucleic acid sequence that encodes IL-12 p35 subunit and the nucleic acid sequence that encodes IL-12 p40 subunit are on the same plasmid. The ‘036 claims teach wherein the nucleic acid sequence that encodes IL-12 p35 subunit and the nucleic acid sequence that encodes IL-12 p40 subunit are on the same nucleic acid molecule and operably linked to different promoters. The ‘036 claims teach wherein the nucleic acid sequence that encodes IL-12 p35 subunit and the nucleic acid sequence that encodes IL-12 p40 subunit are on the same plasmid and operably linked to different promoters. The ‘036 claims teach further comprising a nucleic acid sequence that encodes an immunogen. The ‘036 claims teach further comprising a nucleic acid sequence that encodes an immunogen from a pathogen selected from the group consisting of: HIV, HPV, HCV, Influenza, Smallpox, Chikungunya, foot and mouth disease virus, Malaria, human cytomegalovirus, human respiratory syncytial virus, and MRSA. The ‘036 claims teach wherein the nucleic acid sequence that encodes IL-12 p35 subunit and the nucleic acid sequence that encodes IL-12 p40 subunit are incorporated into a viral particle. The ‘036 claims teach further comprising a nucleic acid sequence that encodes one or more proteins selected from the group consisting of: IL-15 and IL-28. Thus, the ‘036 claims anticipate the instant claims, and the ‘036 claims and instant claims are not patentably distinct.
Applicant’s Arguments
Applicant request that the rejection be held in abeyance until claims are deemed allowable in the instant application.
Response to Arguments
Applicant’s arguments have been fully considered but they are not persuasive. Applicant is reminded that a rejection under double patenting precludes the identification of allowable subject matter. MPEP 804 states that a complete response to a nonstatutory double patenting (NDP) rejection is either a reply by applicant showing that the claims subject to the rejection are patentably distinct from the reference claims or the filing of a terminal disclaimer in accordance with 37 CFR 1.321 in the pending application(s) with a reply to the Office action. Such a response is required even when the nonstatutory double patenting rejection is provisional. As filing a terminal disclaimer, or filing a showing that the claims subject to the rejection are patentably distinct from the reference application's claims, is necessary for further consideration of the rejection of the claims, such a filing should not be held in abeyance. Only objections or requirements as to form not necessary for further consideration of the claims may be held in abeyance until allowable subject matter is indicated. Therefore, an application must not be allowed unless the required compliant terminal disclaimer(s) is/are filed and/or the withdrawal of the nonstatutory double patenting rejection(s) is made of record by the examiner. Accordingly, the rejection is maintained.
Claims 68 and 71-82 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 11,241,496. Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are drawn to a composition that comprises a) a nucleic acid sequence that encodes a functional fragment of IL-12 p35 subunit and b) a nucleic acid sequence that encodes a functional fragment of IL-12 p40 subunit, wherein the nucleic acid sequence that encodes a functional fragment of IL-12 p35 subunit is at least 85% homologous to SEQ ID NO:1 and encodes a protein at least 85% homologous to SEQ ID NO:2, and the nucleic acid sequence that encodes a functional fragment of IL-12 p40 subunit is at least 85% homologous to SEQ ID NO:3 and encodes a protein at least 85% homologous to SEQ ID NO:4.
The ’496 claims teach composition for increasing an immune response that comprises a) a nucleic acid sequence that encodes IL-12 p35 subunit and b) a nucleic acid sequence that encodes IL-12 p40 subunit, wherein the nucleic acid sequence that encodes IL-12 p35 subunit is at least 90% identical to SEQ ID NO:1 and encodes a protein at least 90% identical to SEQ ID NO:2, and the nucleic acid sequence that encodes IL-12 p40 subunit is at least 90% identical to SEQ ID NO:3 and encodes a protein at least 90% identical to SEQ ID NO:4. The ‘496 claims teach comprising the nucleic acid sequence that encodes IL-12 p35 subunit is at least 97% identical to SEQ ID NO:1 and encodes a protein at least 97% identical to SEQ ID NO:2, and the nucleic acid sequence that encodes IL-12 p40 subunit is at least 97% identical to SEQ ID NO:3 and encodes a protein at least 97% identical to SEQ ID NO:4. The ‘496 claims teach comprising the nucleic acid sequence that encodes IL-12 p35 subunit is at least 98% identical to SEQ ID NO:1 and encodes a protein at least 98% identical to SEQ ID NO:2, and the nucleic acid sequence that encodes IL-12 p40 subunit is at least 98% identical to identical SEQ ID NO:3 and encodes a protein at least 98% identical to SEQ ID NO:4. The ‘496 claims teach comprising the nucleic acid sequence that encodes IL-12 p35 subunit is at least 99% identical to SEQ ID NO:1 and encodes a protein at least 99% identical to SEQ ID NO:2, and the nucleic acid sequence that encodes IL-12 p40 subunit is at least 99% identical to SEQ ID NO:3 and encodes a protein at least 99% identical to SEQ ID NO:4. The ‘496 claims teach formulated for delivery to an individual using electroporation. The ‘496 claims teach wherein the nucleic acid sequence that encodes IL-12 p35 subunit is on a different nucleic acid molecule than the nucleic acid sequence that encodes IL-12 p40 subunit. The ‘496 claims teach wherein the nucleic acid sequence that encodes IL-12 p35 subunit is on a plasmid and the nucleic acid sequence that encodes IL-12 p40 subunit is on a different plasmid. The ‘496 claims teach wherein the nucleic acid sequence that encodes IL-12 p35 subunit and the nucleic acid sequence that encodes IL-12 p40 subunit are on the same nucleic acid molecule. The ‘496 claims teach wherein the nucleic acid sequence that encodes IL-12 p35 subunit and the nucleic acid sequence that encodes IL-12 p40 subunit are on the same plasmid. The ‘496 claims teach wherein the nucleic acid sequence that encodes IL-12 p35 subunit and the nucleic acid sequence that encodes IL-12 p40 subunit are on the same nucleic acid molecule and operably linked to different promoters. The ‘496 claims teach wherein the nucleic acid sequence that encodes IL-12 p35 subunit and the nucleic acid sequence that encodes IL-12 p40 subunit are on the same plasmid and operably linked to different promoters. The ‘496 claims teach further comprising a nucleic acid sequence that encodes an immunogen. The ‘496 claims teach further comprising a nucleic acid sequence that encodes an immunogen from a pathogen selected from the group consisting of: HIV, HPV, HCV, Influenza, Smallpox, Chikungunya, foot and mouth disease virus, Malaria, human cytomegalovirus, human respiratory syncytial virus, and MRSA. The ‘496 claims teach wherein the nucleic acid sequence that encodes IL-12 p35 subunit and the nucleic acid sequence that encodes IL-12 p40 subunit are incorporated into a viral particle. The ‘496 claims teach further comprising a nucleic acid sequence that encodes one or more proteins selected from the group consisting of: IL-15 and IL-28. Thus, the ‘496 claims anticipate the instant claims, and the ‘496 claims and instant claims are not patentably distinct.
Applicant’s Arguments
Applicant request that the rejection be held in abeyance until claims are deemed allowable in the instant application.
Response to Arguments
Applicant’s arguments have been fully considered but they are not persuasive. Applicant is reminded that a rejection under double patenting precludes the identification of allowable subject matter. MPEP 804 states that a complete response to a nonstatutory double patenting (NDP) rejection is either a reply by applicant showing that the claims subject to the rejection are patentably distinct from the reference claims or the filing of a terminal disclaimer in accordance with 37 CFR 1.321 in the pending application(s) with a reply to the Office action. Such a response is required even when the nonstatutory double patenting rejection is provisional. As filing a terminal disclaimer, or filing a showing that the claims subject to the rejection are patentably distinct from the reference application's claims, is necessary for further consideration of the rejection of the claims, such a filing should not be held in abeyance. Only objections or requirements as to form not necessary for further consideration of the claims may be held in abeyance until allowable subject matter is indicated. Therefore, an application must not be allowed unless the required compliant terminal disclaimer(s) is/are filed and/or the withdrawal of the nonstatutory double patenting rejection(s) is made of record by the examiner. Accordingly, the rejection is maintained.
Claim Status
No claims are allowed.
Conclusion
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SANDRA CARTER whose telephone number is (571)272-2932. The examiner can normally be reached 8:00-5:00 pm.
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/SANDRA CARTER/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674
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