DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims Status
Applicant’s amendment submitted 6/3/2026 is acknowledged. Claim 6 is canceled.
Amended claims 1-5 and 7-9 are under examination on the merits.
Response to Arguments
Applicant’s arguments, see pp. 1-2, filed 6/3/2026, with respect to objections to the claims, and rejections under 35 U.S.C. §§102-103 have been fully considered and are persuasive. The objections and rejections have been withdrawn.
New rejections under 35 U.S.C. §§112(a)-(b) are raised below.
Objections Removed
The previous objections are hereby withdrawn due to Applicant’s amendment filed 6/3/2026 and the new rejections raised herein:
Claim objections: Claims 6 and 7 as being dependent upon a rejected base claim.
New Objections
Claim 1 is objected to because of the following informalities: claim 1 has a typographical mistake on line 8, where it recites “a nucleic sequence”, which should instead read “a nucleic acid sequence”. Appropriate correction is required.
Rejections Removed
The previous rejections are hereby withdrawn due to Applicant’s amendment filed on 6/3/2026:
35 U.S.C. §102: Claims 1-2, 4-5 & 8-9 under 35 U.S.C. 102(a)(1)as being anticipated by Kinney (WO 2019036617 A1, published 2/21/2019).
35 U.S.C. §103: Claim 3 under 35 U.S.C. 103 as being unpatentable over Kinney (WO 2019036617 A1, published 2/21/2019), as applied to claims 1-2, 4-5 & 8-9 above, and further in view of Liu, et al. (Sci Rep. 2017 May 19;7(1):2193. doi: 10.1038/s41598-017-02460-2. PMID: 28526819; hereinafter referred to as “Liu”).
New Rejections
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.
Written Description
Claims 1-5 and 7-9 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for 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 above are drawn to a genus of recombinant flaviviruses comprising: a heterologous reporter cassette, the heterologous reporter cassette having a 5’ end, a nucleotide segment encoding a reporter, and a 3’ end; the 5; end of the reporter cassette encoding 25 to 38 amino acids of an amino terminus of a flavivirus capsid protein; the 3; end of the reporter cassette encoding 25 to 38 amino acids of an amino terminus of the flavivirus capsid protein, wherein the recombinant flavivirus is stable, wherein the flavivirus has a nucleic acid sequence that is at least 98% identical to SEQ ID NO: 13, 15, 17, 19, 21, 23, 25, 27, 29, or 31 (claim 1) or a recombinant flavivirus polyprotein comprising an amino terminal segment comprising a heterologous reporter, the reporter being flanked by an amino terminal first capsid segment corresponding to a capsid sequence comprising 25 to 38 amino terminal amino acids of the flavivirus capsid protein and a carboxy terminal second capsid segment corresponding to a capsid segment comprising 25 to 38 amino acids of the amino terminus of the flavivirus capsid protein, wherein the polyprotein is at least 95% identical to the amino acid sequence of SEQ ID NO: 14, 16, 18, 20, 22, 24, 26, 28, 30, or 32 (claim 8, claim 7 has a similar polyprotein sequence identity requirement).
Because the prior art is silent to any species in these genera, all description of such recombinant flaviviruses and polyproteins must come from the instant disclosure.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
An applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613.
Furthermore, to satisfy the written description requirement for the genus recombinant flaviviruses that have a nucleic acid sequence at least 98% identical to SEQ ID NO: 13, 15, 17, 19, 21, 23, 25, 27, 29, or 31, and flavivirus polyproteins that are at least 95% identical to the amino acid sequence of SEQ ID NO: 14, 16, 18, 20, 22, 24, 26, 28, 30, or 32, Applicant must adequately describe representative vectors to reflect the structural diversity of the claimed genus. See Eli Lilly, 119 F.3d at 1568 (“[N]aming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”); Fiers v. Revel, 984 F.2d 1164, 1171 (Fed. Cir. 1993) (“Claiming all DNA[s] that achieve a result without defining what means will do so is not in compliance with the description requirement; it is an attempt to preempt the future before it has arrived.”).
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 759 F.3d 1285, 111 USPQ2d 1780 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, as here in which flaviviruses and flavivirus polyproteins can have variation in nucleic acid or amino acid sequences, respectively, one must describe a sufficient variety of species to reflect the variation within the genus. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure “indicates that the patentee has invented species sufficient to constitute the gen[us].” See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615. “A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.” One of skill in this art cannot envision the structure of every recombinant flaviviruses that have a nucleic acid sequence at least 98% identical to SEQ ID NO: 13, 15, 17, 19, 21, 23, 25, 27, 29, or 31, and flavivirus polyproteins that are at least 95% identical to the amino acid sequence of SEQ ID NO: 14, 16, 18, 20, 22, 24, 26, 28, 30, or 32. The specification discloses these sequence identifiers, but does not provide representative species regarding mutants (e.g., substitutions, truncations, etc.) thereof. Specifically, the claimed genera read on species other than “wobble” variants, and it is these other species that a person having ordinary skill in the art cannot envision. The instant disclosure includes limited species for each of these species: for nucleic acids at least 98% identical to SEQ ID NOs: 17, 19, 21, 23, 29, and 31, one species each; SEQ ID NOs: 13, 15, 25, and 27, two species each. For amino acid sequences at least 95% identical to SEQ ID NOs: 18, 20, 22, 24, 30, and 32, one species each; SEQ ID NOs: 14, 16, 26, and 28, two species each. Therefore, since limited species are provided to represent these genera, the claims encompassing the same clearly fail the written description requirement.
Functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. See ABBVIE DEUTSCHLAND GMBH & 2 CO. v. JANSSEN BIOTECH, INC., Appeals from the United States District Court for the District of Massachusetts in Nos. 09-CV-11340-FDS, 10-CV-40003-FDS, and 10-CV-40004-FDS, Judge F. Dennis Saylor, IV. See also Ariad, 598 F.3d at 1351 (“[T]he level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology.”); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1352 (Fed. Cir. 2011) (noting the technical challenges in developing fully human antibodies of a known human protein).
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The recitation of a functional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of the genus must be capable of doing, not of the substance and structure of the members.
“Functional” terminology may be used “when the art has established a correlation between structure and function” but “merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing one has invented a genus and not just a species.” Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010).
Even when several species are disclosed, these are not necessarily representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus.”). Thus, when there is substantial variation within the genus, as here, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. Since each genus recited in the instant claims is large, it would be very challenging to describe sufficient species to cover the structures of the entire genus. The disclosed species are certainly not adequate.
Overall, at the time the invention was made, the level of skill for preparing recombinant flaviviruses and polyproteins was high.
A representative number of species has not been taught to describe these genera; one of skill in the art would conclude that applicant was not in possession of the structural attributes of a representative number of species possessed by the members of the genera of recombinant flaviviruses that have a nucleic acid sequence at least 98% identical to SEQ ID NO: 13, 15, 17, 19, 21, 23, 25, 27, 29, or 31, and flavivirus polyproteins that are at least 95% identical to the amino acid sequence of SEQ ID NO: 14, 16, 18, 20, 22, 24, 26, 28, 30, or 32. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genera.
While applicant has described a limited number of species within each of the genera recited, the genera are large and would encompass structures that cannot be visualized from the prior art or instant disclosure. One of skill in this art cannot determine the structures encompassed by the claimed genera only defined by function. Any future recombinant flavivirus or polyprotein structure may or may not be encompassed, and if it is, it would not have been represented in Applicant’s disclosed species. Thus, the described species cannot be considered representative of the recited genera of recombinant flaviviruses that have a nucleic acid sequence at least 98% identical to SEQ ID NO: 13, 15, 17, 19, 21, 23, 25, 27, 29, or 31, and flavivirus polyproteins that are at least 95% identical to the amino acid sequence of SEQ ID NO: 14, 16, 18, 20, 22, 24, 26, 28, 30, or 32. E.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, the claims are rejected here.
As discussed above, an applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613. Therefore, it is recommended that the instant claims be amended to recite complete structural information of the claimed recombinant flaviviruses and flavivirus polyproteins, including full sequences.
Scope of Enablement
Claims 1-5 and 7-9 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a recombinant flavivirus that has a fully defined nucleic acid sequence and amino acid sequences of an encoded polyprotein, both having been tested and shown as functional, does not reasonably provide enablement for similar flaviviruses having sequences that are 98% identical to the recited nucleic acid sequences and 95% identical to the recited amino acid sequence identifiers. 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 or use the invention commensurate in scope with these claims.
The breadth of the claims is recombinant flaviviruses comprising: a heterologous reporter cassette, the heterologous reporter cassette having a 5’ end, a nucleotide segment encoding a reporter, and a 3’ end; the 5; end of the reporter cassette encoding 25 to 38 amino acids of an amino terminus of a flavivirus capsid protein; the 3; end of the reporter cassette encoding 25 to 38 amino acids of an amino terminus of the flavivirus capsid protein, wherein the recombinant flavivirus is stable, wherein the flavivirus has a nucleic acid sequence that is at least 98% identical to SEQ ID NO: 13, 15, 17, 19, 21, 23, 25, 27, 29, or 31 (claim 1) or a recombinant flavivirus polyprotein comprising an amino terminal segment comprising a heterologous reporter, the reporter being flanked by an amino terminal first capsid segment corresponding to a capsid sequence comprising 25 to 38 amino terminal amino acids of the flavivirus capsid protein and a carboxy terminal second capsid segment corresponding to a capsid segment comprising 25 to 38 amino acids of the amino terminus of the flavivirus capsid protein, wherein the polyprotein is at least 95% identical to the amino acid sequence of SEQ ID NO: 14, 16, 18, 20, 22, 24, 26, 28, 30, or 32 (claim 8, claim 7 has a similar polyprotein sequence identity requirement).
The nature of the invention is recombinant flaviviruses that carry reporter cassettes.
The level of skill of one skilled in this art is high.
The specification teaches a number of recombinant flaviviruses that encode a heterologous reporter cassette and have fully defined flavivirus nucleic acid sequences (spec., paras. [0008-0018]) and polyprotein amino acid sequences (spec., paras. [0008-0018]). These teachings do not enable the full breadth of the claims because the claimed sequence variation in the nucleic acid sequence and polyprotein sequence encompasses flaviviruses and polyproteins thereof that would be dysfunctional as viruses and reporters. For example, the claims allow for mutations in promoters, the capsid protein, start codons, or the reporter sequences, any of which could potentially prevent proper expression or function of the claimed flavivirus and gene products thereof.
Variation of the recited nucleic acid and amino acid sequences permits protein mutation. Such mutation is not predictable. The state of the prior art is such that it is well established in the art that protein chemistry is probably one of the most unpredictable areas of biotechnology. For example, replacement of a single “lysine” residue 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 (Burgess et al., J of Cell Bio. 111:2129-2138, 1990). In transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen (Lazar et al. Molecular and Cellular Biology 8:1247-1252, 1988). As these references illustrate, it is unpredictable that a polypeptide variant of a known target protein binder will also bind said target. It is also unpredictable that they would bind said target in the same way, having the same effect on the target (i.e. inhibit or activate). Ju (Proceedings of the National Academy of Sciences, U.S.A., Vol. 88, Pg. 2658-2662, 1991) teaches that the interleukin 1 receptor (IL-1R) antagonist IL-1ra is a naturally occurring protein with no agonist activity in vitro or in vivo (Abstract). However, substitution of a single amino acid lysine145 to aspartic acid changes the property of this peptide to a partial agonist of IL-1R (Abstract). Thus, even a single substitution can change the biological property of a peptide.
This substitution need not be at a position where said residue would contact the target protein. Baker (Immunity, Vol. 13, Pg. 475-484, 2000) teaches that Tax-peptide is an agonist of the of T cell activity (Abstract). However, mutation of proline at position 6 of this peptide to alanine creates a T cell antagonist (Abstract). Importantly, this residue does not contact the T cell receptor (Abstract).
In another case, Huang (The Journal of Biological Chemistry, Vol. 272, No. 43, Pg. 27155-27159, 1997) teaches that conjugation of peptides to other proteins can change their biological properties. They teach that multiple conjugation of the peptide TGFβ1 (residues 41-65) to carrier proteins enhances its antagonist activity but also confers partial agonist activity as well (Abstract). Thus, the chemical context of a biologically active peptide is also important.
Truncation of proteins can also lead to adverse effects on protein structure and thus protein function. Martindale (Nature Genetics, Vol. 18, Pg. 150-154, 1998) teaches that truncation of huntingtin leads to aggregate development which compromises cell viability (Abstract). Nonaka (Human Molecular Genetics, Vol. 18, No. 18, Pg. 3353-3364, 2009) teaches that truncation of TDP-43 to its C-terminal fragments causes abnormally phosphorylated and ubiquitinated inclusions of the protein (Abstract). Taken together, not just any truncation of a protein will yield a soluble, functional, protein fragment.
In summary, these examples teach that the biological function of peptide variants is unpredictable because even a single mutation can abolish activity or give a different function. For example, agonist and antagonist peptides can be interconverted through conjugation or mutagenesis. Importantly, binding can still occur after mutation or conjugation in the literature examples provided above, illustrating that a simple show of binding is not predictive of the nature of a peptide’s biological activity. This point is underlined by Montrose-Rafizadeh (The Journal of Biological Chemistry, Vol. 272, Pg. 21201-21206, 1997) who teaches that receptor binding does not predict agonist or antagonist activity (Pg. 21205, Column 2, Paragraph, first full, Sentence, first).
Thus, the state of the art recognized that it would be highly unpredictable that a specific mutated recombinant flavivirus or polyprotein encoded thereby would properly function. The minimal structure which the skilled artisan would consider predictive of the function of a reporter would be the full length sequence of the reporter cassette that has the requisite binding function. One of skill in the art would neither expect nor predict the appropriate functioning of the recombinant flaviviruses or flaviviral polyproteins comprising a heterologous reporter cassette as broadly as currently claimed.
In view of the lack of the predictability of the art to which the invention pertains as evidenced by Burgess, Lazar, Ju, Baker, Huang, Martindale, Nonaka, Montrose-Rafizadeh, and Mendoza, the lack of guidance and direction provided by applicants, and the absence of working examples, undue experimentation would be required to make and use functional recombinant flaviviruses that encompass up to 2% nucleic acid sequence variation and 5% polyprotein amino acid variation, absent a specific and detailed description in applicant’s specification of how to effectively practice this and absent working examples providing evidence which is reasonably predictive that the claimed flaviviruses and polyproteins are functional, commensurate in scope with the claimed invention.
Not knowing, absent further experimentation, which modifications function and which do not, when, as set forth above, even a single change of an encoded amino acid can unpredictably affect flavivirus and polyprotein structure and function, leads to one having no predictability or expectation of success for the function of any given mutation. Such random experimentation to identify at a later time what structure or fragment or modification is or is not functional and is embraced by Applicant’s claims is undue experimentation. This affects all claims that can mutate any flavivirus nucleic acid sequence or polyprotein encoding or comprising a heterologous reporter by reciting percent identity, for example claims 1-5 and 7-9.
Since the art teaches that it is unpredictable whether or not peptide variants of known modulators will function as such and it is also unpredictable that even a known modulatory peptide that functions in vitro will function in vivo, and the specification does nothing to ameliorate these concerns, one would be burdened with undue experimentation to use the products of the instant claims as broadly as they are currently claimed.
Note that an enabling disclosure for the preparation and use of only a few analogs of a product does not enable all possible analogs where the characteristics of the analogs are unpredictable. See Amgen Inc. v. Chugai Pharmaceutical Co. Ltd. (18 USPQ 2d 1027 (CAFC 1991)).
35 U.S.C. §112(b) – Indefiniteness
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-5 and 7 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites the limitation “wherein the recombinant flavivirus is stable” on line 7. The metes and bounds of the term “stable” are unclear. The examiner’s previous interpretation of the term “stable” is withdrawn in favor of the broadest reasonable interpretation. The specification does not provide an explicit definition for “stable”, but instead indicates “NanoLuc-tagged flaviviruses were stable after ten rounds of cell culture passaging” (spec., para. [0006]). Given BRI, it is unclear if “stable” refers to a shelf-life stability, or genetic stability through passage (i.e., capacity to maintain particular cassettes or genes during passage). Additionally, “stable” in each of those interpretations is subjective, without clear metes or bounds. Ten rounds of passage with detectable cassette does not appear to be required for stability but merely exemplary of it. The specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Claims 2-5 and 7 depend on claim 1 but do not provide clarity, and are thus also indefinite.
Art-free Subject Matter
SEQ ID NOs: 13-32 are free of the prior art of record.
Conclusion
No claim is allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEFFREY MARK SIFFORD whose telephone number is 571-272-7289. The examiner can normally be reached 8:30 a.m. - 5:30 p.m. ET with alternating Fridays off.
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/JEFFREY MARK SIFFORD/Examiner, Art Unit 1671
/Michael Allen/Supervisory Patent Examiner, Art Unit 1671
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