Ex Parte RathnachalamDownload PDFPatent Trial and Appeal BoardNov 17, 201713940122 (P.T.A.B. Nov. 17, 2017) Copy Citation United States Patent and Trademark Office UNITED STATES DEPARTMENT OF COMMERCE United States Patent and Trademark Office Address: COMMISSIONER FOR PATENTS P.O.Box 1450 Alexandria, Virginia 22313-1450 www.uspto.gov APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO. 13/940,122 07/11/2013 Radhakrishnan Rathnachalam 173-000110US 3202 22798 7590 11/21/2017 QUINE INTELLECTUAL PROPERTY LAW GROUP, P.C. 2033 CLEMENT AVENUE SUITE 200 ALAMEDA, CA 94501 EXAMINER MCDONALD, JENNIFER SUE PITRAK ART UNIT PAPER NUMBER 1674 NOTIFICATION DATE DELIVERY MODE 11/21/2017 ELECTRONIC Please find below and/or attached an Office communication concerning this application or proceeding. The time period for reply, if any, is set in the attached communication. Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the following e-mail address(es): info@quinelaw.com gbaker@quinelaw.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte RADHAKRISHNAN RATHNACHALAM Appeal 2017-001110 Application 13/940,122 Technology Center 1600 Before FRANCISCO C. PRATS, JEFFREY N. FREDMAN, and RYAN H. FLAX, Administrative Patent Judges. FREDMAN, Administrative Patent Judge. DECISION ON APPEAL This is an appeal1 under 35 U.S.C. § 134(a) involving claims to a therapeutic virus (TV), capable of inhibiting propagation of a target virus. The Examiner rejected the claims as indefinite, as anticipated, and as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm. Statement of the Case Background The present inventions are in the field of methods and constructs useful in targeting viruses with disabling virus like particles. The particles are directed to include disabled essential enzymes so they can only replicate in the presence of rescuing enzymes of a target virus. The particles can include 1 Appellant identifies the Real Party in Interest as the inventor, Radhakrishnan Rathnachalam (see App. Br. 1). Appeal 2017-001110 Application 13/940,122 sequences encoding an miRNA against a highly conserved sequence in an essential gene, and include a copy of the essential gene modified to avoid binding by the miRNA. The particles can be used in methods to inhibit an infections [Vc] target virus from replicating. (Spec. 12). The Claims Claims 1—9, 20 and 21 are on appeal. Independent claim 1 is representative and reads as follows: 1. A therapeutic virus (TV), capable of inhibiting propagation of a target virus, the TV comprising: a) an inactive first essential gene for propagation of the TV in a normal host of the target virus or the absence of the first essential gene for the propagation of TV in the normal host of the target virus, wherein the TV is adapted so that the TV can not propagate alone in the normal host of the target virus but the TV can propagate in the presence the target virus providing an active form of the first essential gene; b) a sequence encoding a pre-miRNA, wherein an miRNA product from the pre-miRNA is adapted to have a first affinity for a highly conserved sequence of a second essential gene in the target virus, whereby the miRNA inhibits translation of the highly conserved sequence; and, c) a modified version of the second essential gene comprising a modified version of the highly conserved target sequence, which modified version of the second essential gene is adapted to transcribe into an RNA transcript for which the miRNA sequence has a second affinity lower than the first affinity and which RNA transcript encodes an active form of the target sequence peptide product, or wherein the miRNA sequence has a second affinity lower than the first affinity for the modified version of the second essential gene which encodes an active form of the target sequence peptide product; 2 Appeal 2017-001110 Application 13/940,122 whereby the TV is adapted to not propagate in the normal host without the presence of the target virus, and adapted so that the target virus can not propagate in the normal host in the presence of the TV. The Issues2,3 A. The Examiner rejected claims 1—9, 20 and 21 under 35 U.S.C. § 112, second paragraph (Ans. 2-4). B. The Examiner rejected claim 9 under 35 U.S.C. § 102(b) as anticipated by Genbank Accession number U69584.12 3 4 (Ans. 4—5). C. The Examiner rejected claims 1—8, 20 and 21 under 35 U.S.C. § 103(a) as obvious over McSwiggen,5 Zamore,6 and Humeau7 (Ans. 5—6). A. 35 U.S.C. § 112, second paragraph The Examiner finds several claim terms indefinite. We will separately address each of these claim terms. 2 The Examiner withdrew anticipation rejections over Cheng or Zamore and withdrew an obviousness rejection over McSwiggen and Zamore (see Examiner’s Answer mailed Aug. 24, 2007 (“Ans.”) at 7). 3 Appellant appeals the Examiner’s objection of claim 9 (App. Br. 3). While the Examiner did not reiterate the objection, the Examiner also did not enter the amendment that would cure the objection (see Advisory Action 10/23/2015) and did not identify the objection as withdrawn (Ans. 7). The propriety of the Examiner’s objection relates to petitionable matters and not to appealable matters. Objections to formal elements of the claim are petitionable under 37 C.F.R. § 1.181 to the Director of the USPTO. See MPEP § 706.01; the “Board will not hear or decide issues pertaining to objections and formal matters which are not properly before the Board.” Accordingly, we will decline to address the objections of record. 4 Genbank U69584.1, Blast Alignment. 5 McSwiggen et al., US 8,008,472 B2, issued Aug. 30, 2011. 6 Zamore et al., US 2006/0293267 Al, published Dec. 28, 2006. 7 Humeau et al., US 2003/0026791 Al, published Feb. 6, 2003. 3 Appeal 2017-001110 Application 13/940,122 “adapted to ” The Examiner finds claim 1 “sets forth several limitations indicating that the TV ‘is adapted’ for certain functions. See, inter alia, lines 5, 9, 14, 20, 21 of claim 1. The structure of the claimed TV is not clear because the meaning of ‘adapted’ is not provided” (Ans. 2). The Examiner finds the cited portions of the instant disclosure do not provide a clear definition of the structure of the claimed TV that is, for example, “adapted so that the TV can not propagate alone in the normal host of the target virus but the TV can propagate in the presence the target virus providing an active form of the first essential gene” as in the instant claim 1. (Ans. 12). Appellant contends even internal to the claim itself, definite ways of providing the adapted virus are identified. For example, the TV has an inactive first essential gene for propagation alone in the normal host of the target virus. The claim itself makes it apparent the adaption not to propagate is the lack of an essential gene. (App. Br. 4). We find that Appellant has the better position because the Examiner does not identify any ambiguities introduced by the phrase “adapted to.” Indeed, the “adapted to” phrase appears to have little import to the interpretation of the claim(s) as whole. For example, we see no ambiguity or difference in meaning between the phrase “wherein the TV is adapted so that the TV can not propagate” and a phrase where “adapted to” is removed so as to read “where in the TV can not propagate.” [The indefiniteness] requirement is not a demand for unreasonable precision. The requirement, applied to the real world of modem technology, does not contemplate in every 4 Appeal 2017-001110 Application 13/940,122 case a verbal precision of the kind found in mathematics. Nor could it do so in a patent system that actually works, in practice, to provide effective protection for modern-day inventions. Rather, how much clarity is required necessarily invokes some standard of reasonable precision in the use of language in the context of the circumstances. In re Packard, 751, F.3d 1307, 1313 (Fed. Cir. 2014). Here, while unnecessary, the phrase “adapted to” does not render the claims indefinite. “increase mismatches ” The Examiner finds: “Claim 3 recites the limitation ‘increase mismatches’ in line 4. There is insufficient antecedent basis for this limitation in the claim. There are no mismatches required from which the number of mismatches may be increased” (Ans. 3—4). Appellant contends There are no mismatches required from which the number of mismatches may be increased. That is, there may be no mismatches (e.g., zero) and this may be increased by adding one. No matter the original mismatches in a particular instance, one of skill can definitely increase the mismatches with the miRNA by adjusting the sequence of the target sequence of interest. (App. Br. 5). We find that Appellant has the better position because the phrase “increase mismatches” is reasonably understood as adding at least one mismatch to a preexisting nucleic acid relative to a binding miRNA, irrespective of the number of mismatches already present between the two nucleic acids. To the extent that a starting point is not provided, that is not indefinite, just broadly encompassing any number of preexisting mismatches including zero prior mismatches. 5 Appeal 2017-001110 Application 13/940,122 “the target normal host ” The Examiner finds: “Claim 6 recites the limitation ‘the target normal host’ in line 1. There is insufficient antecedent basis for this limitation in the claim” (Ans. 4). Appellant contends “Parent claim 1 presents ‘a normal host of the target virus’ which definitely can be the only thing the target normal host could reasonably be referring to. Antecedence is present” (App. Br. 5). We find Appellant has the better position because the natural antecedent basis for “the target normal host” in claim 6 is the “a normal host” found in the first clause of claim 1. The Examiner does not explain why the term is ambiguous or otherwise unclear. “underlined sequences ” The Examiner finds: Claim 9 recites the limitation ‘underlined sequences’ in line 2. There is insufficient or ambiguous antecedent basis for this limitation in the claim. Sequences depicted in Figure 30 have numbered nucleotides that do not correspond to the numbers of SEQ ID NO:84. Several sequences within Figure 30 have underlining of different styles. (Ans. 4). Appellant contends “one of skill, in light of the original specification can unambiguously determine what sequences of either Figure 30, or identical SEQ ID NO 84, are identified by underlining in original Figure 30. There can be no confusion” (App. Br. 5). We find that the Examiner has the better position. Claim 9 recites a therapeutic virus with “85% identity to the sequence of Figure 30 (SEQ ID NO: 84) and retaining at least 95% identity to underlined sequences.” 6 Appeal 2017-001110 Application 13/940,122 However, it is indefinite whether the therapeutic virus must have 95% identity to the totality of underlined sequences or have 95% identity to each of the many different underlined sequences individually. That is, if the prior art has 100% identity to all of the sequences except the “ATG” to which it has 0% identity, the overall identity would exceed 95%, but there would be no identity with one of the many underlined sequences. Therefore, it is indefinite what is meant by “95 % identity to underlined sequences” in claim 9. B. 35 U.S.C. § 102(b) over Genbank U69584 The Examiner finds “U69584.1 meets the structural limitations specified in the instant claim 9. Therefore, U69584.1 anticipates the instant claim 9. See the alignment of SEQ ID N0:84 with U69584.1” (Final Act. 6). Appellant did not address this issue in the Appeal Brief, but contends in the Reply Brief that: Claim 9 is a dependent claim and cannot be anticipated without a description of disclosure of all limitations of the parent claims. The raised Genebank sequence can not anticipate the claim, e.g., because it does not disclose (and it is not alleged) the several structural features interacting as required in parent claim 1. (Reply Br. 2). Appellant further contends: Even if the cited HIV sequence were to be 85% identical to the therapeutic virus of the claim, it is not necessarily (inherently) so, e.g., that, the Genebank sequence cannot propagate without a wild type (which the Genebank sequence appears to be), and include an miRNA functioning as required in the parent claim. Not all limitations are inherently present. (Id.). 7 Appeal 2017-001110 Application 13/940,122 We find that the Examiner has the better position. Claim 9, as found in the Appeal Brief, is reproduced below: 9. (Previously presented) A TV having at least 85% identity to the sequence of Figure 30 (SEQ ID NO: 84) and retaining at least 95% identity to underlined sequences, wherein the TV inhibit replication of HIV when both the TV and HIV are present in the same cell. (App. Br. 15). Contrary to Appellant’s contention, claim 9 plainly does not depend from claim 1, and therefore does not incorporate any structural limitations from claim 1. We therefore find Appellant’s argument regarding structural limitations found in claim 1 unpersuasive. With regard to the identity argument, the Examiner has provided an alignment between SEQ ID NO: 84 and Genbank Accession No. U69584 showing a 98% identity between the sequences (see Office Action Appendix mailed 8/11/2015). The Examiner has therefore provided evidence that the virus disclosed in Genbank Accession No. U69584 satisfies the 95% structural identity requirement recited by claim 9. We find that the “wherein the TV inhibit replication of HIV when both the TV and HIV are present in the same cell” limitation is an intended use recitation, not a structural limitation. Even if we treated this functional recitation as have some structural consequence, Schreiber teaches that writing a claim that mixes structural and functional limitations comes at a price. In re Schreiber, 128 F.3d 1473 (Fed. Cir. 1997). (“[CJhoosing to define an element functionally, i.e., by what it does, carries with it a risk.”). The price is that when the structural limitations are met by a single prior art reference, and when the examiner “has reason to believe” that the prior art reference inherently teaches the functional limitation, the burden shifts to the 8 Appeal 2017-001110 Application 13/940,122 patent applicant to show that the functional limitation cannot be met by the single prior art reference. Id. See also In re Best, 562 F.2d 1252, 1254-55 (CCPA 1977) (“[Wjhere the Patent Office has reason to believe that a functional limitation asserted to be critical for establishing novelty in the claimed subject matter may, in fact, be an inherent characteristic of the prior art, it possesses the authority to require the applicant to prove that the subject matter shown to be in the prior art does not possess the characteristic relied on.”). Here, the Examiner demonstrates that Genbank Accession No. U69584 satisfies all of the structural elements recited by the claim and, therefore, reasonably relies upon the inherency doctrine for the functional language. Appellants provide no evidence in rebuttal, only argument. See In re Pearson, 494 F.2d 1399, 1405 (CCPA 1974) (“Attorney’s argument in a brief cannot take the place of evidence.”). C. 35 U.S.C. § 103(a) over McSwiggen, Zamore, and Humeau The issue with respect to this rejection is: Does the evidence of record support the Examiner’s conclusion that the combination of McSwiggen, Zamore, and Humeau renders the therapeutic virus of claim 1 obvious? Findings of Fact 1. Humeau teaches “improved conditionally replicating vectors .... A conditionally replicating vector is characterized by a capacity to replicate only in a host cell that is permissive for replication of the vector. The improved vectors provided hereby have increased safety by being at reduced risk of regaining replication competency” (Humeau 117). 9 Appeal 2017-001110 Application 13/940,122 2. Humeau teaches an improved conditionally replicating vector comprises at least one nucleic acid sequence, the presence, transcription or translation of which confers to the vector in a replication- permissive host cell a selective advantage over a wild-type strain of virus corresponding to the virus from which the vector was derived.... In another preferred embodiment, the conditionally replicating vector is a retrovirus .... (Humeau 18—19). 3. Humeau teaches “contacting a host cell. . . with a conditionally replicating vector, which is capable of being replicated only in a host cell permissive for the replication of the vector, the presence, transcription or translation of which inhibits the replication of the wild-type strain of virus in the host cell” (Humeau 1163). 4. Humeau teaches a “further preferred embodiment is a non- pathogenic crHIV vector that is non pathogenic because it does not contain any combination of the viral accessory protein sequences (such as, but not limited to, Vif, Vpu, Vpr or Nef, or combinations or fragments thereof) that would make the vector pathogenic ... the sequences may be present but transcriptionally silent or not translated” (Humeau 174). 5. Humeau teaches “a conditionally replicating vector according to the invention is a virus (which preferably is the same type of virus as the infection being treated) that replicates only upon complementation with a wild-type strain of virus (or a helper) or when wild-type virus infects cells containing conditionally replicating vector genomes” (Humeau 172). 10 Appeal 2017-001110 Application 13/940,122 6. Humeau teaches: For example, the vector of the invention may contain an antisense sequence which destroys both the competing vector and the helper, yet the vector would have a selective advantage for replication because it additionally contains a second first nucleotide sequence (e.g. a promoter that produces more vector RNA over competing vector RNA, the copy number of the vector in the transduced cell is higher than the competing genome, or a packaging signal that is present in the vector but not in a helper) that provides the conditionally replicating vector with the overall selective advantage. (Humeau 120). 7. Humeau teaches the “vector can be protected from cleavage by degenerating its sequence to not be targeted by a ribozyme or antisense sequence” (Humeau 121). 8. Humeau teaches a conditionally replicating vector according to the invention, in the presence of a complementary wild-type superinfection, also functions as a type of “viral delivery vector” whereby, for example, multiple rounds of crHIV infection (i.e., in the presence of concurrent infection with wild-type HIV) can ensue. Such a vector provides a source of virus for more than one round of viral replication and thus infection of other cells. (Humeau 1 91). 9. Humeau teaches a “category of a nucleic acid sequence that confers a selective advantage to a vector containing the sequence as compared with a wild-type strain of virus includes ... an antiviral nucleic acid sequence” where such “antiviral agents include, but are not limited to, antisense molecules, RNA decoys . . . modifiers and modulators of RNA . . . 11 Appeal 2017-001110 Application 13/940,122 nucleotide sequences or molecules that modify or modulate splicing” (Humeau 1117). 10. Humeau teaches an “antisense molecule can be expressed from crHIV RNA that preferentially binds to genomic wild-type RNA, thereby providing the crHIV RNA with a selective advantage for packaging into progeny virions” (Humeau 1120). 11. Humeau teaches: Such antisense molecules preferably bind to genomic wild-type RNA and not vector RNA, providing the vector with a selective advantage over the wild-type virus. A preferred region for generating an antisense molecule in an HIV derived vector, for example, is from the envelope region (env), the Tat or Rev protein regions, the accessory gene regions (Vif, Nef, Vpr, Vpu), regions of Gag that are 3 ’ to the Nsi I restriction enzyme site on pNL4-3, and the regions of Pol that do not contain the a 545 base region in Pol. (Humeau 1121). 12. Humeau teaches an example in which “nonpathogenic crHIVs are able to spread to uninfected cells that are susceptible to HIV infection (e.g., CD4+ cells) in the presence of wild-type helper virus. In this manner, selective packaging and spread of crHIV interferes with wild-type HIV replication” (Humeau 173). 13. McSwiggen teaches “small nucleic acid molecules, such as . . . micro-RNA (miRNA). . . capable of mediating RNA interference (RNAi) against HIV gene expression. Such small nucleic acid molecules are useful ... in providing compositions for treatment of traits, diseases and conditions that can respond to modulation of HIV expression” (McSwiggen 2:6—14). 12 Appeal 2017-001110 Application 13/940,122 14. McSwiggen teaches: “RNA interference can also involve small RNA (e.g., micro-RNA or miRNA) mediated gene silencing, presumably though cellular mechanisms that regulate chromatin structure and thereby prevent transcription of target gene sequences” (McSwiggen 72:41—45). 15. McSwiggen teaches “combination therapies .... The treatment of subjects with siNA molecules can also include combinations of different types of nucleic acid molecules, such as enzymatic nucleic acid molecules (ribozymes), allozymes, antisense, 2,5-A oligoadenylate, decoys, and aptamers” (McSwiggen 79:14—23). 16. Zamore teaches: “Two types of small (-19-23 nt), noncoding RNAs trigger RNA silencing in eukaryotes: small interfering RNAs (siRNAs) and microRNAs (miRNAs, also known as small temporal RNAs (stRNAs)). Both siRNAs and miRNAs are produced by the cleavage of double-stranded RNA (dsRNA) precursors by Dicer” (Zamore 14). 17. Zamore teaches “that the mRNA expressed by a virus can be recruited by an RNA-silencing agent to silence the expression of a target mRNA in a cell infected with said virus” (Zamore | 8). 18. Zamore teaches: In certain embodiments, the mRNA targeting moiety may be designed to target viral mRNAs (i.e. mRNAs encoded by viral genes) encoding a viral protein in order to induce RNA silencing of viral and/or host genes. For example, the mRNA targetting moiety may be designed to silence target viral miRNAs expressed by any of the viruses described herein. Viral mRNAs which may be targeted by the RNA-silencing agents of the invention include, but are not limited to, viral capsid proteins, viral envelope proteins, viral enzymes affecting interaction of the virus with the host protease (e.g. neuraminidases, endoglycosidases ), viral enzymes transcribing 13 Appeal 2017-001110 Application 13/940,122 the viral genome into RNA (e.g. DNA and RNA-dependent RNA polymerases. (Zamore 1 89). Principles of Law “The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” KSRInt’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007). Analysis We adopt the Examiner’s findings of fact and reasoning regarding the scope and content of the prior art (Ans. 5—6; FF 1—18 (highlighting certain facts)) and agree that the claims are obvious over Humeau, McSwiggen, and Zamore. We address Appellant’s arguments below. Appellant contends the combination of references does not teach all limitations of the claims, e.g., a therapeutic virus, wherein the TV has an inactive essential gene, and the TV has an encoded miRNA with a higher affinity for a target virus essential gene than for its own version of the gene, and wherein TV is adapted to not propagate in the normal host without the presence of the target virus, and adapted so that the target virus ca[n] not propagate in the normal host in the presence of the TV. (App. Br. 8). Appellant further contends “the Humeau reference does not cure the defect of missing limitations in the rejection” (App. Br. 9). We are not persuaded. Humeau teaches a conditionally replicating vector (FF 1) where the “conditionally replicating vector is a retrovirus” (FF 2) that “inhibits the replication of the wild-type strain of virus” (FF 3). Humeau teaches the conditionally replicating vector may comprise inactive essential genes required for propagation in a normal host, 14 Appeal 2017-001110 Application 13/940,122 specifically teaching the vector “is non pathogenic because it does not contain any combination of the viral accessory protein sequences (such as, but not limited to, Vif, Vpu, Vpr or Nef, or combinations or fragments thereof) . . . the sequences may be present but transcriptionally silent or not translated” (FF 4). Humeau does teach that the conditionally replicating vector “replicates only upon complementation with a wild-type strain of virus” that provides the active essential gene (FF 5). Humeau teaches that the conditionally replicating vector may encode inhibitory sequences including antisense, ribozymes, RNA decoys, and others (FF 6, 7, 9) where the inhibitory sequence inhibits translation of an essential gene, and Humeau specifically teaches a “preferred region for generating an antisense molecule in an HIV derived vector, for example, is from the envelope region (env), the Tat or Rev protein regions, the accessory gene regions (Vif, Nef, Vpr, Vpu)” (FF 11). Humeau teaches that the conditionally replicating vector may encode a modified form of the essential gene where “antisense molecules preferably bind to genomic wild-type RNA and not vector RNA, providing the vector with a selective advantage over the wild-type virus” (FF 11). Humeau teaches that this different binding affinity for the conditionally replicating vector may be obtained “by degenerating its sequence to not be targeted by a ribozyme or antisense sequence” (FF 7). Thus, Humeau teaches a conditionally replicating vector that “replicates only upon complementation with a wild-type strain of virus” (FF 5), but “interferes with wild-type [virus] replication” (FF 12). While Humeau does not list miRNA in the list of inhibitory sequences that includes antisense, ribozymes, RNA decoys and others, it does disclose 15 Appeal 2017-001110 Application 13/940,122 using antisense molecules (FF 6, 7, 9), and the Examiner relies upon Zamore and McSwiggen to demonstrate that miRNA would have been a known equivalent of antisense RNA (see Ans. 17). McSwiggen teaches “micro-RNA (miRNA). . . capable of mediating RNA interference (RNAi) against HIV gene expression” (FF 13) and further teaches “treatment of subjects with siNA molecules can also include combinations of different types of nucleic acid molecules, such as enzymatic nucleic acid molecules (ribozymes), allozymes, antisense” (FF 15). Thus, McSwiggen recognizes the equivalent inhibitory functionality of siRNA molecules such as miRNA and antisense or ribozyme inhibitors as disclosed by Humeau (FF 7). In addition, Zamore teaches miRNAs function silence viral genes (FF 17). We, therefore, agree with the Examiner that it would have been obvious to substitute miRNA inhibition for antisense or ribozyme inhibition because these were known equivalent methods for inhibiting viral gene expression (FF 6, 7, 9, 13, 15, 17). To the extent that Appellant implies explicit or express motivation is required, the “obviousness analysis cannot be confined by the formalistic conception of the words teaching, suggestion, and motivation, or by overemphasis on the importance of... the explicit content of issued patents.” KSR, 550 U.S. at 419. Therefore, the ordinary artisan interested in using Humeau’s conditionally replicating vector to inhibit wild-type virus replication (FF 12) would have reasonably selected any known “antiviral nucleic acid sequence” (FF 9). This substitution is merely a “predictable use of prior art elements according to their established functions.” KSR, 550 U.S. at 417. No secondary consideration evidence for 16 Appeal 2017-001110 Application 13/940,122 the combination has been provided rebutting the Examiner’s prima facie case of obviousness. Appellant contends Further, the method of Humeau claim 7 requires the presence of the vector in the host cell before the wild type virus, while this is not required of the TV. This demonstrates that the structures of the TV function differently than those of Humeau’s vectors. TV of the present claims propagates (therapeutic virus - virions), not merely replicates nucleic acids in the host cell. (App. Br. 9). We find this argument unpersuasive because claim 1 is drawn to a product or composition, not a method, and does not require any particular order in combining the components of its composition. See In re Self, 671 F.2d 1344, 1348 (CCPA 1982) (“[AJppellant’s arguments fail from the outset because . . . they are not based on limitations appearing in the claims.”) In addition, Humeau does teach that the vector can propagate in the host cell, teaching the “vector provides a source of virus for more than one round of viral replication and thus infection of other cells” (FF 8). Appellant contends: McSwiggin does not teach at least the use of miRNA. The cited paragraph 4 in Zamore only mentions the existence of miRNAs. miRNAs were known in the art to function in the normal regulation of peptide expression in a cell, but not for preventing propagation of viruses. Even limiting discussion to this single missing limitation of many, the motive for combination of references is inadequate. (App. Br. 10). We find this argument unpersuasive because it substantially focuses on whether it would have been obvious to modify McSwiggen with Zamore 17 Appeal 2017-001110 Application 13/940,122 without addressing Humeau and also seeks to limit the analysis to McSwiggen as a “primary” reference. However, “where a rejection is predicated on two references each containing pertinent disclosure ... we deem it to be of no significance, but merely a matter of exposition, that the rejection is stated to be on A in view of B instead of on B in view of A, or to term one reference primary and the other secondary.” In re Bush, 296 F.2d 491,496 (CCPA1961). Here, Humeau is relied upon for all of the claim elements including inhibitory RNA sequences other than the use of miRNA (FF 1—12) and McSwiggen and Zamore demonstrate that miRNA is a known and predictable equivalent type of inhibitory RNA sequence (FF 13—18). “If a person of ordinary skill can implement a predictable variation, § 103 likely bars its patentability.” KSR, 550 U.S. at 417. Appellant contends “incorporating the miRNAs of Zamore unobviously changes the principle of operation in the primary McSwiggin reference and changes the function of the incorporated Zamore miRNAs” (App. Br. 10). Appellant contends: “Introducing such an miRNA to McSwiggin or Zamore would change the principle of operation from HIV RNA targeted binding to RISC recruitment of RISC proteins in a way that would be expected not to function” (App. Br. 11). Appellant further contends: “Regardless of what secondary reference is used, the principle of operation would have to change in Humeau to mimic the present claims” (Reply Br. 3). We find this argument unpersuasive because Humeau suggests a conditionally replicating vector that constitutes a therapeutic virus with each of the structural limitations of claim 1 other than the use of miRNA, 18 Appeal 2017-001110 Application 13/940,122 specifically, as the inhibitory RNA sequence (FF 1—12), and this is would have been obvious because McSwiggen and Zamore demonstrate that miRNA was a known and predictable equivalent type of inhibitory RNA sequence (FF 13—18). The teachings of McSwiggen and Zamore reasonably render selection of alternative modes of RNA inhibition obvious in the absence of a secondary consideration. Our conclusion finds substantial support in the underlying facts of the KSR decision, where the Supreme Court was not persuaded by the Federal Circuit’s reliance upon a statement from an “expert that claim 4 was nonobvious because, unlike in Rixon, the sensor was mounted on the support bracket rather than the pedal itself.” KSR, 550 U.S. at 415. That is, like the current case where a substitution of miRNA for inhibitory RNAs such as antisense or ribozyme would have been obvious, some reconstruction of the prior art elements in KSR amounting to a change in the operation of the pedal sensor from mechanical to electrical would have been required to arrive at the claimed invention. The Court, however, found that “if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond his or her skill.” Id. at 417. Appellant submits a late argument regarding claim 20 that “[regarding dependent claim 20, Appellants note that there has never been an argument made on the record using facts to allege obviousness” (Reply Br. 3). We are not persuaded. Claim 20 was included in the Examiner’s statement of rejection in the Final Office Action (see Final Act. 7) and in the 19 Appeal 2017-001110 Application 13/940,122 Examiner’s Answer (see Ans. 5). Humeau suggests that the conditionally replicating vector virus is packaged in the same capsids as those of the wild- type virus (FF 12) as required by claim 20. Moreover, because this argument is untimely, the Examiner did not have the opportunity to respond. See Ex parte Borden, 93 USPQ2d 1473, 1474 (BPAI 2010) (informative) (“The reply brief is not an opportunity to make arguments that could have been made during prosecution, but were not. Nor is the reply brief an opportunity to make arguments that could have been made in the principal brief on appeal to rebut the Examiner’s rejections, but were not.”). Conclusion of Law The evidence of record supports the Examiner’s conclusion that the combination of McSwiggen, Zamore, and Humeau renders the therapeutic virus of claim 1 obvious. SUMMARY In summary, we reverse the rejection of claims 1—8, 20, and 21 under 35 U.S.C. § 112, second paragraph. We affirm the rejection of claim 9 under 35 U.S.C. § 112, second paragraph. We affirm the rejection of claim 9 under 35 U.S.C. § 102(b) as anticipated by Genbank Accession number U69584.1. We affirm the rejection of claim 1 under 35 U.S.C. § 103(a) as obvious over McSwiggen, Zamore, and Humeau. Claims 2—8, 20, and 21 fall with claim 1. No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a). AFFIRMED 20 Copy with citationCopy as parenthetical citation