Detailed Office 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 .
37 C.F.R. § 1.114
A request for continued examination under 37 C.F.R. § 1.114, including the fee set forth in 37 C.F.R. § 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 C.F.R. § 1.114, and the fee set forth in 37 C.F.R. § 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 C.F.R. § 1.114.
Status of the Claims
Acknowledgement is hereby made of receipt and entry of the communication filed 24 March, 2026. Claims 1, 4-7, and 12-18 are pending in the instant application. Claims 13-18 stand withdrawn from further consideration by the Examiner, pursuant to 37 C.F.R. § 1.142(b), as being drawn to a non-elected invention.
Claim Objections
Claims 1 and 4-7 are objected to because of the following informalities: claim 1 references multiple steps including d) and a final step e). However, the claim recites “d) a subgenomic promoter upstream of one or more of said one or more open reading frames, e) a poly(A) cassette downstream of said one or more open reading frames.” This should read “d) a subgenomic promoter upstream of one or more of said one or more open reading frames, and e) a poly(A) cassette downstream of said one or more open reading frames.” Appropriate correction is required.
35 U.S.C. § 112(b)
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.
Claims 1 and 4-7 are rejected under 35 U.S.C. § 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, regards as the invention. Two separate requirements are set forth under this statute: (1) the claims must set forth the subject matter that applicants regard as their invention; and (2) the claims must particularly point out and distinctly define the metes and bounds of the subject matter that will be protected by the patent grant.
The claims are directed toward an alphavirus-derived RNA vector comprising one or more open reading frames (ORFs), encoding a chimeric antigen receptor (CAR) targeting a tumor antigen, wherein all alphaviral structural genes have been removed from the alphavirus-derived RNA vector, wherein the alphavirus-derived RNA vector comprises:
a) a 5'-cap,
b) a 5' replication recognition sequence, that can be recognized by an alphaviral replicase, wherein the 5' replication recognition sequence does not contain any initiation codon,
c) a first open reading frame encoding the CAR targeting a tumor antigen, a chain of the CAR or a functional alphavirus replicase compatible to the 5' replication recognition sequence, wherein the 5' replication recognition sequence and the first open reading frame encoding a protein of interest do not overlap and wherein the initiation codon of the first open reading frame is in the 5'→3' direction of the RNA replicon and is the first initiation codon,
d) a subgenomic promoter upstream of one or more of said one or more open reading frames,
e) a poly(A) cassette downstream of said one or more open reading frames.
The claim is vague and indefinite because the precise structural organization and functional activities of the alphavirus-derived vector are not readily manifest. For example, the claim (1) references a first open reading frame encoding a CAR, or chain thereof, or a functional alphavirus replicase. However, the preamble references an alphavirus-derived vector comprising an ORF encoding a CAR. Thus, the optional claim language would encompass constructs that don’t encode a CAR. Alternatively, does the construct encode a first ORF encoding a CAR and additional ORFs encoding various alphavirus replicase proteins (e.g., nsp1, nsp2, nsp3, and nsp4)? Furthermore, it is not readily manifest if this construct is a cis-replicon (self-amplifying) or a trans-replicon (trans-amplifying). Is the alphavirus replicase encoded by this construct or is it provided in trans? Does the construct simply contain the 5’ replication recognition sequence lacking the first ATG initiation codon (ΔATG), a subgenomic alphavirus promoter (e.g., 26S), followed by one or more transgenes? Appropriate clarification is required. Applicants are directed toward Figs. 1 and 6 from the drawings. Applicants’ representative is invited to contact the Examiner to discuss suggested allowable claim language.
35 U.S.C. § 112(a)
The following is a quotation 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.
Written Description
Claims 1 and 4-7 stand rejected under 35 U.S.C. § 112(a), 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, at the time the application was filed, had possession of the claimed invention. Amgen, Inc. v. Sanofi, 872 F.3d 1367, 124 U.S.P.Q.2d 1354 (Fed. Cir. 2017). AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc., 759 F.3d 1285, 111 U.S.P.Q.2d 1780 (Fed. Cir. 2014). Univ. of Rochester v. G.D. Searle & Co., Inc., 358 F.3d 916, 920, 69 U.S.P.Q.2d 1886, (Fed. Cir. 2004). Enzo Biochem, Inc. v. Gen-Probe, Inc., 296 F.3d 1316, 63 U.S.P.Q.2d 1609, (Fed. Cir. 2002). Regents of the University of California v. Eli Lilly & Co., 119 F.3d 1559, 43 U.S.P.Q.2d 1398, (Fed. Cir. 1997). Fiers v. Revel Co., 984 F.2d 1164, 25 U.S.P.Q.2d 1601, (Fed. Cir. 1993). Amgen, Inc. v. Chugai Pharmaceutical Co., 927 F.2d 1200, 18 U.S.P.Q.2d 1016, (Fed. Cir. 1991). In re Rasmussen, 650 F.2d 1212, 211 U.S.P.Q. 323 (C.C.P.A. 1981). In re Wertheim, 541 F.2d 257, 191 U.S.P.Q. 90 (C.C.P.A. 1976).
As previously set forth, the crux of the statutory requirement governing written description is whether one skilled in the art, familiar with the practice of the art at the time of the filing date, could reasonably have found the later claimed invention in the specification as filed. In re Kaslow, 707 F.2d 1366, 1375, 217 U.S.P.Q. 1089, 1096 (Fed. Cir. 1983). In re Wilder, 736 F.2d 1516, 1520 222 U.S.P.Q. 349, 372 (Fed. Cir. 1984, cert. denied, 469 U.S. 1209 (1985). Texas Instruments, Inc. v. International Trade Comm’n, 871 F.2d 1054, 1063, 10 U.S.P.Q.2d 1257, 1263 (Fed. Cir. 1989). Moreover, the courts have stated that the evaluation of written description is highly fact-specific, and that broadly articulated rules are inappropriate. In re Wertheim, 541 F.2d 257, 263, 191 U.S.P.Q. 90, 97 (C.C.P.A. 1976). In re Driscoll, 562 F.2d 1245, 1250, 195 U.S.P.Q. 434, 438 (C.C.P.A. 1977). It is also important to remember that the true issue in question is not whether the specification enables one of ordinary skill in the art to make the later claimed invention, but whether or not the disclosure is sufficiently clear that those skilled in the art will conclude that the applicant made the invention having the specific claim limitations. Martin v. Mayer, 823 F2d 500, 505, 3 U.S.P.Q.2d 1333, 1337 (Fed. Cir. 1987).
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor has possession of the claimed invention. See, e.g., Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 U.S.P.Q.2d at 1116. An applicant shows possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention. Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 U.S.P.Q.2d 1961, 1966 (Fed. Cir. 1997). The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art-recognized correlation or relationship between the structure of the invention and its function. A biomolecule sequence described only by a functional characteristic, without any known or disclosed correlation between that function and the structure of the sequence, normally is not a sufficient identifying characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence. A lack of adequate written description issue also arises if the knowledge and level of skill in the art would not permit one skilled in the art to immediately envisage the product claimed from the disclosed process. Fujikawa v. Wattanasin, 93 F.3d 1559, 1571, 39 U.S.P.Q.2d 1895, 1905 (Fed. Cir. 1996).
The amended claims are directed toward an alphavirus-derived RNA vector comprising one or more open reading frames (ORFs), encoding a chimeric antigen receptor (CAR) targeting a tumor antigen, wherein all alphaviral structural genes have been removed from the alphavirus-derived RNA vector, wherein the alphavirus-derived RNA vector comprises:
a) a 5'-cap,
b) a 5' replication recognition sequence, that can be recognized by an alphaviral replicase, wherein the 5' replication recognition sequence does not contain any initiation codon,
c) a first open reading frame encoding the CAR targeting a tumor antigen, a chain of the CAR or a functional alphavirus replicase compatible to the 5' replication recognition sequence, wherein the 5' replication recognition sequence and the first open reading frame encoding a protein of interest do not overlap and wherein the initiation codon of the first open reading frame is in the 5'→3' direction of the RNA replicon and is the first initiation codon,
d) a subgenomic promoter upstream of one or more of said one or more open reading frames,
e) a poly(A) cassette downstream of said one or more open reading frames.
The claims are still directed toward a large genus of alphavirus vectors. As previously set forth, the alphaviruses include a large genus of genotypically/phenotypically distinct viruses (Gould et al., 2010; Weaver et al., 2012). They include both Old World and New World viruses. Representative members include the following: the Barmah Forest virus complex (comprising Barmah Forest virus); Eastern equine encephalitis complex (comprising seven antigenic types of Eastern equine encephalitis virus); Middelburg virus complex (comprising Middelburg virus); Ndumu virus complex (comprising Ndumu virus); Semliki Forest virus complex (comprising Bebaru virus, Chikungunya virus, Mayaro virus and its subtype Una virus, O'Nyong Nyong virus, and its subtype Igbo-Ora virus, Ross River virus and its subtypes Bebaru virus, Getah virus, Sagiyama virus, Semliki Forest virus and its subtype Me Tri virus); Venezuelan equine encephalitis complex (comprising Cabassou virus, Everglades virus, Mosso das Pedras virus, Mucambo virus, Paramana virus, Pixuna virus, Rio Negro virus, Trocara virus and its subtype Bijou Bridge virus, Venezuelan equine encephalitis virus); Western equine encephalitis complex (comprising Aura virus, Babanki virus, Kyzylagach virus, Sindbis virus, Ockelbo virus, Whataroa virus, Buggy Creek virus, Fort Morgan virus, Highlands J virus, Western equine encephalitis virus); and some unclassified viruses including Salmon pancreatic disease virus; Sleeping Disease virus; Southern elephant seal virus; Tonate virus. More preferably, the alphavirus is selected from the group consisting of Semliki Forest virus complex (comprising the virus types as indicated above, including Semliki Forest virus), Western equine encephalitis complex (comprising the virus types as indicated above, including Sindbis virus), Eastern equine encephalitis virus (comprising the virus types as indicated above), Venezuelan equine encephalitis complex (comprising the virus types as indicated above, including Venezuelan equine encephalitis virus) (see also specification, pp. 49 and 50). Thus, the claims encompass an inordinate number of variant alphavirus RNA replicons. Many of these viruses have different host specificities, tissue tropisms, and promoter requirements. However, the disclosure fails to provide adequate guidance with respect to suitable promoter and replication recognition sequences from different alphaviruses. Limited working embodiments were provided wherein trans-replicon vectors comprising the VEEV 5’ UTR and modified CSE 2 region were utilized. However, there was no description or comparison of any other alphaviral genomic regions, particularly with respect to the 5’ UTR and CSE 2 regions. There was no reduction to practice of RNA replicons generated from other alphavirus, either Old World or New World.
The claims also encompass a large genus of chimeric antigen receptors (CARs). The only structural requirements set forth require an antigen-binding domain, transmembrane domain, and T-cell signaling domain. The antigen-binding domain could encompass a multitude of different molecules. However, for any given CAR to be effective, the target antigen and antigen binding domain (typically an scFv) need to be identified (Kosti et al., 2018). The disclosure references a limited number of examples wherein RNA replicons comprising CARs were generated. However, it doesn’t appear to disclose any structural information about the actual receptors employed. The structure of the antigen-binding domain were not provided and the target antigen were not clearly set forth.
Clearly the recitation of a few limited working embodiments directed toward solely toward VEEV constructs, is insufficient to support the full breadth of the patent protection desired. The disclosure does not describe the isolation and characterization of any additional alphavirus vectors (e.g., EEEV, SFV, SINV, etc.). The disclosure does not disclose the structural requirements of different alphavirus polymerase recognition sequences. It has been suggested that different alphaviruses might employ different 5’ recognition sequences for RNA synthesis, as well as, utilize different host factors (Pietilä et al., 2017). Accordingly, when all the aforementioned factors are considered in toto, the skilled artisan would reasonably conclude that Applicants were not in possession of a sufficient number of species to support the full breadth of the patent protection desired.
Applicants submit that a safe platform for adoptive immunotherapy has been developed using a novel replicative RNA format to achieve high-level and prolonged expression of therapeutic CARs. It was argued that additional limitations have been incorporated that satisfy the written description requirement. The claimed structural modification encompassed by the claims are common to all alphaviruses. Additional generic structural features of alphaviruses was also set forth (e.g., genome size of 11-12 kb; 5’-cap structure; 3’-poly(A) tail; etc.). Applicants’ arguments have been carefully considered but are not deemed to be persuasive for the reasons of record set forth supra. Applicants’ representative is invited to contact the Examiner to discuss suggested allowable claim language.
Correspondence
Any inquiry concerning this communication should be directed to Jeffrey S. Parkin, Ph.D., whose telephone number is (571) 272-0908. The Examiner can normally be reached Monday through Friday from 10:00 AM to 6:00 PM. A message may be left on the Examiner's voice mail service. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner are unsuccessful, the Examiner's supervisor, Janet L. Andres, Ph.D., can be reached at (571) 272-0867. Direct general status inquiries to the Technology Center 1600 receptionist at (571) 272-1600.
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Respectfully,
/JEFFREY S PARKIN/Primary Examiner, Art Unit 1671 01 April, 2026