DETAILED ACTION
Disposition of Claims
Claims 1-24 are pending.
Examiner’s Note
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US20240123049A1, Published 04/18/2024.
Applicant is encouraged to utilize the new web-based Automated Interview Request (AIR) tool for submitting interview requests; more information can be found at https://www.uspto.gov/patent/laws-and-regulations/interview-practice.
Optional Authorization to Initiate Electronic Communications
The Applicant’s representative may wish to consider supplying a written authorization in response to this Office action to correspond with the Examiner via electronic mail (e-mail). This authorization is optional on the part of the Applicant’s representative, but it should be noted that the Examiner may not initiate nor respond to communications via electronic mail unless and until Applicant’s representative authorizes such communications in writing within the official record of the patent application. A sample authorization is available at MPEP § 502.03, part II. If Applicant’s representative chooses to provide this authorization, please ensure to include a valid e-mail address along with said authorization.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 08/18/2025, 02/29/2024, and 08/03/2023 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Notably, the disclosure statement filed lists a Search Report. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
Claim Objections
Claim 9 is objected to because of the following informalities: the definition of the abbreviation “HDV” is not provided. For clarity, it is requested that the first recitation of an abbreviation within a claim set be preceded by its full-length name (i.e. … hepatitis delta virus (HDV)-like ribozyme...).
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b); Second Paragraph
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.
Claim 1 is 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.
Regarding claim 1, the phrases “such as”, "preferably", and “more preferably” render the claim indefinite because it is unclear whether the limitations following the phrases are part of the claimed invention. See MPEP § 2173.05(d). One suggestion is to amend the claim so that the limitation(s) following these terms are set forth in dependent claims that further limit this instant claim.
For at least these reasons, claim 1 is rejected on the grounds of being indefinite.
Claim 2 is 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.
Regarding claim 2, the phrases "preferably", “including”, “such as”, and “particularly” render the claim indefinite because it is unclear whether the limitations following the phrases are part of the claimed invention. See MPEP § 2173.05(d). One suggestion is to amend the claim so that the limitations following these terms are set forth in dependent claims that further limit this instant claim.
For at least these reasons, claim 2 is rejected on the grounds of being indefinite.
Claim 3 is 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 3 is drawn to the expression construct according to claim 1, which is linear or circular; particularly, the construct is a linear RNA, wherein a 5' cap structure or an IRES sequence is provided in the 5' end of the RNA to drive translation of downstream coding sequence; or the construct is a circular RNA, wherein an IRES sequence is provided upstream of the RNA polymerase coding unit to drive translation of the RNA polymerase coding unit.
To begin with, the phrase "particularly" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). One suggestion is to amend the claim so that the limitations following these terms are set forth in dependent claims that further limit this instant claim.
Additionally, with the claim further stating that the construct is linear RNA as in line 3 or the construct is circular RNA in line 6, the antecedent basis of these limitations is not readily clear as the claim in lines 1-2 only notes the construct to be linear or circular, but does not clarify if the construct is RNA or DNA.
For at least these reasons, claim 3 is rejected on the grounds of being indefinite.
Claim 4 and dependent claim 16 thereof 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.
Regarding claim 4, the phrase "preferably not" renders the claim indefinite because it is unclear whether the limitations following the phrase are or are not part of the claimed invention. See MPEP § 2173.05(d). One suggestion is to amend the claim so that the limitations regarding this term are set forth in dependent claims that further limit this instant claim.
Claim 16, which depends upon claim 4, is drawn to wherein the replication initiating element is capable of being recognized by the RNA polymerase and guiding the replication of the RNA polymerase; and preferably, the replication initiating element and the RNA polymerase are derived from the same virus or from different viruses, more preferably from the same virus. First, the phrases "preferably" and “more preferably” render claim 16 indefinite because it is unclear whether the limitations following the phrase are or are not part of the claimed invention. See MPEP § 2173.05(d). Second, claim 16 provides for “the replication initiating element” (singular) while claim 4 provides for “replication initiating elements” (plural), so it is unclear if claim 16 is meant to reference a single particular replication initiating element or all of the replication initiating elements of claim 4.
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant Claim 4 is rejected on the grounds of being indefinite. Claim 16 is also rejected since it depends from claim 4, but does not remedy these deficiencies of claim 4.
Claim 5 is 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.
Regarding claim 5, the phrases "preferably" and “more preferably” render the claim indefinite because it is unclear whether the limitations following the phrases are part of the claimed invention. See MPEP § 2173.05(d). One suggestion is to amend the claim so that the limitations following these terms are set forth in dependent claims that further limit this instant claim.
Additionally, in line 3, it recites that the upstream replication initiating element would more preferably comprise CSE1, CSE2, and CSE3 sequences, but only CSE1 and CSE3 were mentioned previously in the claim, making the antecedent basis of CSE2 unclear.
Finally, it is unclear what is meant by the abbreviation “CSE”. At ¶[0110] of the specification, “CSE” is noted as standing for “common conserved sequence”, while at ¶[0119-0120] it is for a “conserved sequence element”, while a search of the art notes CSE1 to be an export receptor for importin alpha (SRP1) in yeast. Therefore, it is unclear what exactly the abbreviations “CSE1”, “CSE2”, “CSE3”, and “CSE4” are intended to read upon in the claim.
For at least these reasons, claim 5 is rejected on the grounds of being indefinite.
Claim 7 is 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.
Regarding claim 7, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitations following the phrase are or are not part of the claimed invention. See MPEP § 2173.05(d). One suggestion is to amend the claim so that the limitations regarding this term are set forth in dependent claims that further limit this instant claim.
For at least these reasons, claim 7 is rejected on the grounds of being indefinite.
Claim 9 is 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 9 is drawn to the expression construct according to claim 1, wherein the target protein coding unit is located upstream of the RNA polymerase coding unit, and a self-cleaving hepatitis delta virus (HDV)-like ribozyme is located between the target protein and the RNA polymerase. The HDV-like ribozyme is a small, self-cleaving, non-coding RNA enzyme essential for the replication of the hepatitis delta virus. It catalyzes the cleavage of genomic and antigenomic RNA transcripts into unit lengths during rolling circle replication. Structurally, the ribozyme folds into a compact double-nested pseudoknot structure with four helical regions, and the cleavage reaction is mediated by a general acid-base mechanism, involving a cytosine as a general acid and a metal ion-bound hydroxide ion. The “ribozyme” is therefore an RNA structure, so claiming that it is located between two proteins is confusing. The ribozyme should be between two RNA coding units, and will be interpreted as such.
For at least this reason, claim 9 is rejected on the grounds of being indefinite.
Claim 11 is 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 11 provides for the limitation of “(4) a multiple cloning site and/or a target gene or heterologous nucleotide sequence controlled by the subgenomic promoter;”. However, the wording of this section of the claim is confusing due to the use of “and/or” and the use of “or” between “target gene” and “heterologous nucleotide sequence”. Further, it is unclear if only the heterologous nucleotide sequence is controlled by the subgenomic promoter (SGP), if the target gene is to be controlled by the subgenomic promoter, or if anything inserted into the MCS is to be controlled by said SGP. One suggestion to clarify item (4) is to claim “(4) a multiple cloning site, a target gene, and/or a heterologous nucleotide sequence, wherein the subgenomic promoter controls expression of the target gene, heterologous nucleotide sequence, or any further gene which may be subsequently inserted into the MCS;”.
Further, in claim 11, the “3' UTR and 3' polyA” are claimed as only present to “ensure the stability of RNA and the effective replication of the target gene.” It is unclear if these elements are intended to only aid in replication of the “target gene”, or if they are to also aid in replication of any heterologous nucleotide sequence or any other gene which may be inserted into the MCS of item (4).
For at least these reasons, claim 11 is rejected on the grounds of being indefinite.
Claim 13 is 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.
Regarding claim 13, the phrases “particularly”, "preferably", “more preferably” render the claim indefinite because it is unclear whether the limitations following the phrases are part of the claimed invention. See MPEP § 2173.05(d). One suggestion is to amend the claim so that the limitations following these terms are set forth in dependent claims that further limit this instant claim.
Further “Venezuelan equine encephalitis complex” and “Western equine encephalitis complex” describe a group of viruses. A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 13 recites the broad recitation of “Western equine encephalitis complex”, and the claim also recites Sindbis virus, Whataroa virus, Fort Morgan virus (and variant Buggy Creek virus), aura virus, and highlands J virus which are narrower statements of the range/limitation. Additionally, claim 13 recites the broad recitation of “Venezuelan equine encephalitis complex”, and the claim also recites Venezuelan equine encephalitis virus (VEEV), Mosso das Pedras virus, Everglades virus, Mucambo virus, Tonate virus, Pixuna virus, Cabassou virus, and Rio Negro virus, which are narrower statements of the range/limitation. The claim is considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
For at least these reasons, claim 13 is rejected on the grounds of being indefinite.
Claim 15 is 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.
Regarding claim 15, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitations following the phrase are or are not part of the claimed invention. See MPEP § 2173.05(d). One suggestion is to amend the claim so that the limitations regarding this term are set forth in dependent claims that further limit this instant claim.
Additionally, it is unclear if the “a mutant thereof” refers to the “any gene” or “5’UTR”. Additionally, claim 1 does not provide that the “RNA polymerase” is from a virus, making the antecedent basis of this limitation unclear.
For at least these reasons, claim 15 is rejected on the grounds of being indefinite.
Claim 17 is 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.
Regarding claim 17, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitations following the phrase are or are not part of the claimed invention. See MPEP § 2173.05(d). One suggestion is to amend the claim so that the limitations regarding this term are set forth in dependent claims that further limit this instant claim.
Additionally, it is unclear if the “a mutant thereof” refers to the “any gene” or “3’UTR”. Additionally, claim 1 does not provide that the “RNA polymerase” is from a virus, making the antecedent basis of this limitation unclear.
For at least these reasons, claim 17 is rejected on the grounds of being indefinite.
Claim 19 is 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.
Regarding claim 19, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitations following the phrase are or are not part of the claimed invention. See MPEP § 2173.05(d). One suggestion is to amend the claim so that the limitations regarding this term are set forth in dependent claims that further limit this instant claim.
For at least these reasons, claim 19 is rejected on the grounds of being indefinite.
Claim 22 is 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 22 is drawn to a vaccine composition comprising the expression construct according to claim 1, wherein the target protein is an antigen capable of eliciting a protective immune response, such as an antigen derived from humans, animals, plants, viruses, bacteria and/or parasites. Regarding claim 22, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
For at least these reasons, claim 22 is rejected on the grounds of being indefinite.
Claim Rejections - 35 USC § 112(d); Fourth Paragraph
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 6 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 6 is drawn to wherein the target protein coding unit is located downstream or upstream of the RNA polymerase coding unit. This claim does not further limit claim 6 in any notable fashion, as the definition of “upstream” and “downstream” is provided for in the application as anywhere 5’ or 3’ to the element it is describing (¶[0094]). As the “target protein coding unit” and the “RNA polymerase coding unit” are both described as being a part of the expression construct, it is inherent to such a system that one unit would inevitably be “upstream” or “downstream” of the other. One suggestion is to have the position be more restrictive, in that the target protein coding unit is within a certain number of nucleotides upstream or downstream, which would further limit the claim upon which it depends.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Interpretation
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
Claim 1 is drawn to an expression construct of cis-replicon, comprising an RNA polymerase coding unit and a target protein coding unit,
wherein the RNA polymerase coding unit comprises a nucleic acid fragment encoding an RNA polymerase, and
the target protein coding unit comprises an insertion site (such as a multiple cloning site) for a target protein coding fragment and/or a nucleic acid fragment encoding the target protein; and
the construct is capable of expressing the RNA polymerase and replicating itself dependent on the RNA polymerase in a target cell to provide a template for expressing the target protein; preferably, the replication of the target protein coding unit is more efficiently than the replication of the RNA polymerase coding unit; and more preferably, only the target protein coding unit is replicated.
Further limitations on the expression construct according to claim 1 are wherein said construct is DNA or RNA, and wherein when the construct is RNA, said construct is single-stranded RNA or double-stranded RNA, and when said construct is single-stranded RNA, it is positive strand (+) single-stranded RNA (claim 2); wherein the expression construct is RNA or DNA and is linear or circular; and when the construct is a linear RNA, a 5' cap structure or an IRES sequence is provided in the 5' end of the RNA to drive translation of downstream coding sequence; or when the construct is circular RNA, an IRES sequence is provided upstream of the RNA polymerase coding unit to drive translation of the RNA polymerase coding unit (claim 3); comprising replication initiating elements located both upstream and downstream of the target protein coding unit, wherein the replication initiating elements dependent on the RNA polymerase for the replication of the target protein coding unit; wherein the RNA polymerase coding unit is preferably not located between the upstream replication initiating element and downstream replication initiating element (claim 4), wherein the upstream replication initiating element comprises a CSE1 and/or CSE3 sequence, preferably CSE1 and CSE3 sequences, and more preferably CSE1, CSE2 and CSE3 sequences; and/or the downstream replication initiating element comprises a CSE4 sequence (claim 5); wherein the target protein coding unit is located downstream or upstream of the RNA polymerase coding unit (claim 6); wherein the target protein coding unit is located upstream of the RNA polymerase coding unit, and the target protein and the RNA polymerase are expressed as a fusion protein with a linker between the target protein and the RNA polymerase, wherein the linker comprises a fragment encoding a protease recognition site, and the RNA polymerase is released after the fusion protein is recognized and cleaved by a protease; and preferably, the protease recognition site is a 2A peptide sequence (claim 7); wherein the target protein coding unit is located upstream of the RNA polymerase coding unit, and an IRES sequence is provided between the target protein coding unit and the RNA polymerase coding unit to drive translation of the RNA polymerase coding unit (claim 8); wherein the target protein coding unit is located upstream of the RNA polymerase coding unit, and a self-cleaving HDV-like ribozyme is located between the target protein coding unit and the RNA polymerase coding unit (claim 9); wherein the target protein coding unit is located downstream of the RNA polymerase coding unit, wherein the construct, in the 5'-3' direction, comprises a 5' cap structure or an IRES sequence to drive translation of downstream coding sequence, the RNA polymerase coding unit, the upstream replication initiating element, the target protein coding unit, and the downstream replication initiating element (claim 10), wherein the construct, in the 5'-3' direction, comprises (1) a 5' UTR sequence comprising a 5' cap structure; (2) one or more nucleotide sequences encoding the RNA polymerase; (3) a 5' end recognition sequence and a subgenomic promoter (SGP) that guide the replication of the RNA replicon; 4) a multiple cloning site, a target gene, and/or a heterologous nucleotide sequence, wherein the subgenomic promoter controls expression of the target gene, heterologous nucleotide sequence, or any further gene which may be subsequently inserted into the MCS; (5) a 3' end recognition sequence that guides the replication of the RNA replicon; and (6) a 3' UTR and 3' polyA that ensure the stability of RNA and the effective replication of the target gene (claim 11), wherein the 5' cap structure is a natural 5' cap or a 5' cap analog (claim 14); wherein the expression construct is DNA, and wherein a subgenomic promoter (SGP) is located upstream of the RNA polymerase coding unit (claim 12); wherein the RNA polymerase is a viral replicase, particularly a replicase of an alphavirus, preferably, the alphavirus is selected from the group consisting of Semliki Forest virus, Barmah Forest virus, Chikungunya virus, O'nyong'nyong virus, Ross River virus, Bebaru virus, Getah virus, Sagiyama virus, Mayaro virus, Una virus, Venezuelan equine encephalitis complex or Venezuelan equine encephalitis virus, Cabassou virus, Everglades virus, Mucambo virus, Tonate virus, Pixuna virus, Mosso das pedras virus, Rio Negro virus, Western equine encephalitis complex or Western equine encephalitis virus, Sindbis virus, Aura virus, Whataroa virus, Highlands J virus, Fort Morgan virus, Buggy Creek virus, Eastern equine encephalitis virus, Middelburg virus, Trocara virus, Kyzylagach virus, Ndumu virus, Babanki virus, Norwegian salmonid alphavirus, Salmon pancreatic disease virus, sleeping disease virus and Southern elephant seal virus; and more preferably, the alphavirus is selected from the group consisting of Semliki Forest virus, Venezuelan equine encephalitis virus, Sindbis virus and Chikungunya virus (claim 13); comprising a 5' UTR derived from the 5' UTR of any gene or a mutant thereof, preferably a 5' UTR derived from the same virus as which the RNA polymerase derived from (claim 15); wherein the replication initiating element is capable of being recognized by the RNA polymerase and guiding the replication of the RNA polymerase; and preferably, the replication initiating element and the RNA polymerase are derived from the same virus or from different viruses, more preferably from the same virus (claim 16); comprising a 3' UTR derived from the 3' UTR of any gene or a mutant thereof, preferably a 3' UTR derived from the same virus as which the RNA polymerase derived from (claim 17); comprising a 3' poly(A)(claim 18); wherein the subgenomic promoter is derived from the promoter of a viral structural protein, and preferably, the subgenomic promoter and the RNA polymerase are derived from the same virus (claim 19)
Claim 20 is drawn to a vector comprising or encoding the expression construct according to claim 1.
Claim 21 is drawn to a pharmaceutical composition comprising the expression construct according to claim 1, wherein the target protein is a therapeutic protein.
Claim 22 is drawn to a vaccine composition comprising the expression construct according to claim 1, wherein the target protein is an antigen capable of eliciting a protective immune response, such as an antigen derived from humans, animals, plants, viruses, bacteria and/or parasites.
Claim 23 is drawn to a method for expressing a target protein, comprising introducing the expression construct according to claim 1 into a target cell, wherein the target cell expresses the target protein from the construct.
Claim 24 is drawn to a method of immunization comprising inoculating a subject in need thereof with the expression construct according to claim 1.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-7, 10-11, and 13-24 are rejected under 35 U.S.C. 101 because the claimed invention is directed to wild-type alphaviruses, alphavirus virions, alphavirus genomes, and methods of natural infection from alphaviruses without significantly more. The claims recite “expression constructs” with open-ended claim language that “comprise” an RNA polymerase, which may be a viral replicase, and a sequence encoding a “target protein”. The claims are drawn to vectors which comprise said expression constructs, and methods of expressing a target protein in a host or eliciting an immune response in a host through the introduction or inoculation of said expression constructs in a host. This judicial exception is not integrated into a practical application because, under broadest reasonable interpretation, the “expression construct” can be understood to be a wild-type alphavirus, as alphaviruses encode their own replicases (RNA polymerase) and the “target protein” is not specifically defined as being required to be heterologous to the expression construct (¶[0130]). The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the expression construct, vector, and methods of inoculation are recited at such a high level of generality that they read upon naturally-occurring alphaviruses and methods of natural infection thereof. For instance, the dependent claims regarding the construct read upon elements which are naturally found in an alphavirus genome, such as an RNA genome, namely a single-stranded (+) sense RNA genome that is linear and capped at the 5’ end and polyadenylated (poly(A)) at the 3’ end. Alphaviruses possess several highly conserved sequence elements (CSEs) in their positive-sense single-stranded RNA genomes that are essential for replication. These 4-5 core elements are located at the 5′ and 3′ untranslated regions (UTRs) and within the coding sequence, acting as promoters for viral RNA synthesis and mediating interaction with viral proteins. There are two open reading frames (ORFs) in the alphavirus genome, one encoding for structural and the other encoding for non-structural proteins. The non-structural ORF encodes four proteins (nsP1-nsP4), wherein the four proteins are encoded as a single polypeptide that is subsequently cleaved by the nsP2 protease into individual proteins or intermediate polyproteins. nsP4 is the core RNA-dependent RNA polymerase (RdRp) and, under broadest reasonable interpretation, nsP1-nsP3 can be considered “upstream” of nsP4 and encoded as a “fusion protein” with linkers that encode protease recognition sites. In the linear genome, the ORF encoding the structural genes is downstream of the non-structural proteins. A highly efficient subgenomic (sg) promoter (SGP) exists in the alphavirus genome to control the expression of these structural proteins. It is a conserved 24-nucleotide cis-acting element (CSE) located at the junction between nonstructural and structural coding sequences, which drives the synthesis of subgenomic RNA from an antisense template; therefore, if the “target protein” is a structural protein, the construct of instant claim 10 can read on a natural alphavirus genome as the SGP exists between the nsP4 and structural ORF, and downstream of the structural ORF is a 3’ UTR and polyA tail. As a specific definition of “therapeutic protein” is not provided, the antigenic nature of the alphavirus proteins encoded by the genome can reasonably be considered as “therapeutic proteins” as they can serve to generate therapeutic or prophylactic immune responses against the alphavirus in a host. The compositions (pharmaceutical composition, vaccine composition) do not claim any structural elements in said compositions to distinguish the alphavirus from naturally-occurring alphavirus genomes or virions. The methods of delivery are recited at such a high level of generality that they reasonably read upon natural infection from a wild-type alphavirus, and the further method steps (e.g. encoding “target protein” or eliciting an immune response) are again recited at such a high level of generality that they read upon methods of natural infection.
One suggestion is to insert limitations from claims not included in this rejection into the independent claim to draw the claims to patent eligible subject matter. Another suggestion is to claim specific structural limitations of the expression vector that could not read upon a natural alphavirus (e.g. specifically claim that the “target protein” is a protein that would be heterologous to the expression construct system, claim specific sequences that cannot read upon naturally occurring sequences, etc.) Applicant may also persuasively argue that the claims are drawn to patent eligible subject matter.
Claim Rejections - 35 USC § 112(a); First Paragraph
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 1-20 and 23-24 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 an isolated or purified expression construct, or vector, or host cell, and methods of use thereof, does not reasonably provide enablement for said non-isolated expression construct, or vector, or host cell and methods of use thereof which read upon a transgenic animal, making a transgenic animal, or a transgene therein. 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/or use the invention commensurate in scope with these claims.
The legal considerations that govern enablement determinations pertaining to undue experimentation have been clearly set forth. Enzo Biochem, Inc., 52 U.S.P.Q.2d 1129 (C.A.F.C. 1999). In re Wands, 8 U.S.P.Q.2d 1400 (C.A.F.C. 1988). See also MPEP § 2164.01(a) and § 2164.04. Ex parte Forman 230 U.S.P.Q. 546 (PTO Bd. Pat. App. Int., 1986). The courts concluded that several factual inquiries should be considered when making such assessments including: the quantity of experimentation necessary, the amount of direction or guidance presented, the presence or absence of working examples, the nature of the invention, the state of the prior art, the relative skill of those in that art, the predictability or unpredictability of the art and the breadth of the claims. In re Rainer, 52 C.C.P.A. 1593, 347 F.2d 574, 146 U.S.P.Q. 218 (1965). The disclosure fails to provide adequate guidance pertaining to a number of these considerations as follows:
Nature of the invention/Breadth of the claims. Applicant broadly claims an expression construct, a vector comprising said expression construct, and the method of expressing said expression construct in a host cell. Under broadest reasonable interpretation, the claims read on a cell within a transgenic animal, method of making a transgenic animal, or a transgene therein, given that the term "isolated" is not denoted in describing the host cell, nucleic acid, or vector.
State of the prior art/Predictability of the art. With respect to the unisolated host cells and transgenes as “nucleic acids” or “vectors “of the instant claims discussed above, the state of the art at the time of filing was such that one of skill in the art could not predict the phenotype of transgenics. The art of transgenic animals has for many years stated that the unpredictability lies, in part, with the site or sites of transgene integration into the target genome and that "the position effect" as well as unidentified control elements are recognized to cause aberrant expression of a transgene and possible silencing of host genes, which result in undesirable phenotypes and/or additional health issues in the animal. The elements of the particular construct used to make transgenic animals are also held to be critical, and they must be designed case by case without general rules to obtain good expression of a transgene in the host. Viral vectors, such as Adeno-associated virus (AAV), adenovirus (AdV), and lentiviral/retroviral vectors, can transfer larger amounts of genetic information to a host, but some vectors cannot carry all the required genetic structures for proper expression (e.g. entire gene plus extensive regulatory elements) and certain viral vectors can cause uncontrolled, random integration, which increases the risk of tumorigenesis and inconsistent expression. (See e.g. National Academies of Sciences, Engineering, and Medicine. Heritable Genetic Modification in Food Animals. Washington (DC): National Academies Press (US); 2025 Apr 23. 3, Potential Hazards to Animals and Consumers.; Park F. Physiol Genomics. 2007 Oct 22;31(2):159-73. Epub 2007 Aug 7.; Shakweer WME, et. al. J Genet Eng Biotechnol. 2023 May 9;21(1):55.) Therefore, the field of transgenics was and remains highly unpredictable.
Working examples/Guidance in the Specification. No working example of a transgenic animal is disclosed in the specification. The specification provides guidance towards the generation and use of alphavirus-based expression constructs, namely Semliki forest virus (SFV)-based replicons which comprise a multiple cloning site (MCS) for insertion of heterologous transgenes, such as green fluorescence protein (GFP) or luciferase reporter transgenes, or the receptor binding domain (RBD) of the spike (S) protein of severe acute respiratory syndrome coronavirus type 2 (SARS CoV-2)(¶[0164-0183]). The expression constructs were generated as DNA plasmids, and the resulting RNA expressed in cells was then encapsulated into liposomes and inoculated into mice and resulted in transient expression of SARS CoV-2 RBD, and said mice generated a detectable antibody response against said RBD (¶[0183-0196]). The animals did not show stable transfection/integration of the expression constructs, and required booster doses to raise further immune responses against the RBD.
Amount of experimentation necessary. At the time of filing, the phenotype of a transgene and transgenic cell contained within any animal was unpredictable. The claims as written, encompassing a transgene and cell in a transgenic animal, is not adequately described in the specification as to prevent excessive experimentation by the public to generate and use the invention. Applicants can obviate the instant rejection by amending the claim to clarify that the vector and expression construct are not within a transgenic animal by utilizing the term "isolated" before the recitation of said vector and expression construct. Applicant may consider using purified in such claims if description is appropriate for such a term and it is not redefined away from standard meaning. Method claims using these products should also carry the appropriate adjectives above.
In view of the lack of the predictability of the art to which the invention pertains as evidenced by the art above, the lack of guidance and direction provided by Applicant, and the absence of working examples, undue experimentation would be required to make and use the transgenes and transgenic animals commensurate in scope with the claimed invention with a reasonable expectation of success.
For the reasons discussed above, it would require undue experimentation for one skilled in the art to make and/or use the claimed products.
Claims 1-24 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 DNA vectors carrying a Semliki Forest virus (SFV)-based Cis-Replicon (pVAX1-cis-SFV-neo), namely wherein said vector encodes a RBD of SARS CoV-2 (pVAX1-RBD), and immunogenic compositions comprising RNA expressed from said pVAX1-RBD vector encapsulated in liposomes for eliciting an immune response in a host, does not reasonably provide enablement for any cis-replicon expression construct comprising any RNA polymerase coding unit and any target protein coding unit and any method of use thereof. 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/or use the invention commensurate in scope with these claims.
The legal considerations that govern enablement determinations pertaining to undue experimentation have been clearly set forth. Enzo Biochem, Inc., 52 U.S.P.Q.2d 1129 (C.A.F.C. 1999). In re Wands, 8 U.S.P.Q.2d 1400 (C.A.F.C. 1988). See also MPEP § 2164.01(a) and § 2164.04. Ex parte Forman 230 U.S.P.Q. 546 (PTO Bd. Pat. App. Int., 1986). The courts concluded that several factual inquiries should be considered when making such assessments including: the quantity of experimentation necessary, the amount of direction or guidance presented, the presence or absence of working examples, the nature of the invention, the state of the prior art, the relative skill of those in that art, the predictability or unpredictability of the art and the breadth of the claims. In re Rainer, 52 C.C.P.A. 1593, 347 F.2d 574, 146 U.S.P.Q. 218 (1965). The disclosure fails to provide adequate guidance pertaining to a number of these considerations as follows:
Nature of the invention/Breadth of the claims. The claims are drawn to a cis-replicon expression construct which comprises any RNA polymerase coding unit and any target protein coding unit, and vectors comprising said expression construct and methods of expressing the target protein in a host, especially in order to elicit an immune response. The “RNA polymerase” can be from any source, but is from any alphavirus in further dependent claims. The target protein may be from any source, but in dependent claims is to be an “antigen” from any source or a “therapeutic protein”.
State of the prior art/Predictability of the art. Alphavirus-based vector systems (especially derived from Sindbis, Semliki Forest, and Venezuelan Equine Encephalitis (VEEV) viruses) are powerful tools for rapid, high-level, cytoplasmic gene expression, particularly for vaccines and cancer therapy. These alphavirus-derived vectors (commonly called “replicons” since they are self-amplifying RNA) have been developed for delivery of foreign genetic information into target cells or target organisms. However, they face significant challenges, including high cytotoxicity, transient expression, and safety concerns related to potential replication competence. Cis-acting replicon systems (single molecule) are efficient, but are often restricted by packaging size and high cytotoxicity, while trans-acting replicon systems (split helper) increase safety by reducing recombination risks but often result in lower titers. Alphavirus replication causes severe cytopathic effects (CPE) and apoptosis in mammalian cells, killing the host cell, which limits their use to transient, short-term applications. Due to increased CPE, they cannot be used for long-term gene therapy. While non-cytopathic mutants exist, they are harder to engineer. Another safety concern is the potential for homologous recombination between the vector and helper RNA/DNA during production, resulting in replication-competent virus (RCV). As many alphaviruses are pathogens (e.g., Chikungunya, VEEV), host immunity to the vector itself can reduce efficacy, especially upon re-administration. Finally, developing stable, high-titer packing cell lines for GMP production is difficult due to the CPE of such viruses.
Various methods have been employed to attempt to increase the efficiency of replicon systems. Most alphavirus replicons are attenuated in that they encode their own nonstructural proteins (nsP1-4) required for replication but lack structural proteins for producing new virus particles. Mutations in nsP2 can reduce host cell killing, but the introduction of silent mutations in alphavirus can alter the ability of the virus to replicate due to destruction of secondary RNA structures required for replication. For example, Michel et al. (Michel G, et. al. Virology. 2007 Jun 5;362(2):475-87. Epub 2007 Feb 12.) describe that the introduction of 95 silent mutations into the coding region of nsP1 of the alphavirus Venezuelan encephalitis virus (VEEV) completely abolished the capacity of VEEV to replicate in cells. The use of DNA plasmids to reduce the need for in vitro RNA transcription can improve stability. However, due to the cytotoxic and transient nature of these replicons, the biggest application thus far has been in cancer therapeutics, as the vectors can have a direct cytopathic effect on the tumor itself whilst also delivering therapeutic anti-cancer proteins directly to the tumor sites (Lundstrom K. Viruses. 2009 Jun;1(1):13-25. Epub 2009 Apr 21.)
Working examples. The working examples disclosed in the specification suggest various cis-replicon constructs (See e.g. Figs. 2-3), but only appears to generate the structure shown in Fig. 2A (¶[0085-0087]), which is a linear construct with (in the 5’ to 3’ direction) a 5’ cap, 5’ UTR, viral replicase, CSE1, CSE2, SGP, target gene sequence, CSE4/3’UTR, and 3’ poly A tail. This construct is generated in a DNA plasmid (¶[0167]) and the “base” plasmid is termed “pVAX1-cis-SFV-neo”, wherein the plasmid utilizes Semliki forest virus (SFV) sequences as the “base” for the replicon and has a neo gene (while it is not specifically stated, it is assumed this is the gene for neomycin phosphotransferase II, conferring resistance to aminoglycoside antibiotics like Neomycin, Kanamycin, and G418). The multiple cloning site (where the “target gene” is inserted in Fig. 2A) allows for insertion of heterologous materials into the plasmid, and the selectable markers EGFP and firefly luciferase (Luc) were inserted at these sites (¶[0169-0177]). An unknown sequence of the receptor binding domain (RBD) of the spike protein of SARS-CoV-2 was homologously recombined into the modified expression vector pVAX1 and the cis-replicon pVAX1-cis-SFV-neo by inserting into the multiple cloning site region at the 3′ end of the subgenomic promoter to construct pVAX1-RBD and pVAX1-cis-SFV-neo-RBD (¶[0170]). This DNA plasmid was expressed in vitro, and RNA was isolated from said cells and encapsulated within generically described liposomes (¶[0185-0186]). Said compositions comprising the liposome-RNA mixtures was inoculated into Balb/c mice; as said mice do not appear to have been engineered to express the natural receptor for SARS CoV-2, said mice were analyzed only for their ability to generate antibodies against the SARS CoV-2 RBD (¶[0187-0195].) No other replication constructs from any other alphaviruses were generated, and no other non-viral or non-alphaviral constructs were engineered. All constructs appear to have been generated in the DNA plasmid system noted; none of the other constructs (e.g. Figs. 2b-d; Fig. 3) were generated and tested. The only heterologous genes inserted into the plasmids were neo, EGFP, luc, and RBD. No other non-SFV cleavage or replication sites, such as the 2A, IRES, or HDV, were inserted into the construct. No other UTRs, CSEs, caps, and/or polyA tails were tested. No circular constructs were generated. None of the immunogenic compositions were tested for their ability to generate a sufficient immune response to challenge from any SARS CoV-2 isolate, and only RNA-liposome compositions were tested for their ability to elicit an immune response in any host.
Guidance in the specification. The specification provides guidance towards DNA vectors carrying a Semliki Forest virus (SFV)-based Cis-Replicon (pVAX1-cis-SFV-neo), namely wherein said vector encodes a RBD of SARS CoV-2 (pVAX1-RBD), and immunogenic compositions comprising RNA expressed from said pVAX1-RBD vector encapsulated in liposomes for eliciting an immune response in a host.
Amount of experimentation necessary. Additional research is required in order to determine how effective any cis-replicon comprising the coding information of any RNA polymerase of any origin and any target protein of any origin would be in generating a replicon capable of self-replication. Additional experimentation is required to determine what positioning of said elements would be tolerated, and what additional elements (e.g. UTRs, CSEs, 2A, IRES, HDV, polyA tails, 5’ caps, etc.) from what sources would be useful in the cis-replicon expression vectors as claimed.
In light of the Supreme Court decision in Amgen Inc. et al. v. Sanofi et al., 143 S. Ct. 1243 (2023) (hereafter Amgen), updated guidelines were provided regarding the assessment of enablement (Federal Register, pp. 1563-1566; Pub. Jan. 10, 2024.) In Amgen, the Supreme Court unanimously affirmed that a genus of monoclonal antibodies were not enabled because when a range within a genus is claimed, there must be reasonable enablement of the scope of the range. The Court found in Amgen that due to the large number of possible candidates within the scope of the claims and the specification's corresponding lack of structural guidance, it would have required undue experimentation to synthesize and screen each candidate to determine which compounds in the claimed class exhibited the claimed functionality. In the instantly claimed invention, the breadth of the multiple claimed genera (e.g. target genes, RNA polymerases, UTRs, CSEs, 2A, IRES, HDV, polyA tails, 5’ caps, etc.) and the potential permutations of said elements creates undue experimentation for a skilled artisan to determine which cis-replicons would be enabled due to the high level of uncertainty in the replicon art.
For the reasons discussed above, it would require undue experimentation for one skilled in the art to make and/or use the claimed methods.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-8 and 10-24 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Beissert et. al. (US20200299725A1, Pub. 09/24/2020; hereafter “Beissert”.)
The Prior Art
Beissert teaches an alphavirus-based cis-replicon vector construct that encodes a protein of interest, such as a pharmaceutically active protein, and that said replicon may encode the alphavirus replicase required for replication (entire document; see ¶[0001]; instant claims 1, 6, 13, 20). Said replicon may be RNA or DNA, and may be linear or circular (¶[0021][0084]; instant claims 2-3), and may comprise conserved sequence elements (CSE) of alphavirus genomes, such as CSE1, CSE2, CSE3, CSE4 or variants thereof, and the CSE1 would be at the native 5’ end while CSE3 is found downstream of CSE1 at the SGP start site and CSE4 is found near the 3’ UTR (¶[0164-0171]; instant claims 4-5). Beissert teaches that heterologous alphavirus non-structural proteins may be used, or other proteins of interest may be reporter proteins, pharmaceutically active peptides or proteins, or inhibitors of IFN signaling, and the heterologous proteins may be encoded as a single polypeptide separated by 2A cleavage sites and possibly under the control of a subgenomic promoter (¶[0238-0240]). As shown by the cartoons, the transgenes may be downstream or upstream of the replicase (nsP4)(Fig. 1; instant claims 6-7). Beissert teaches that internal ribosomal entry sites (IRES) may be utilized (¶[0320]; instant claim 8), and that 5’ caps (¶[0312-0313]; instant claim 14), 5’ UTRs (¶[0055][0131][0147][0261]; instant claim 15), CSEs1-4, SGP (¶[0175][0261-0262]), and 3’ UTR and polyA tails (¶[0055][0132]; instant claims 10, 17-19) may be present, with at least one structure comprising all of these elements as arranged in instant claims 11-12 and 16. Beissert teaches pharmaceutical compositions which comprise the replicon vectors (¶[0384-0387]; instant claim 21), such as vaccines (¶[0432][0438]; instant claim 22). Said vectors may be introduced into a target cell to express the heterologous gene product (¶[0433]; instant claim 23) or can be used in methods of immunization (¶[0437-0438]; instant claim 24).
For at least these reasons, Beissert teaches every limitation of instant claims 1-8 and 10-24, and anticipates the invention encompassed by said claims.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Beissert as applied to claims 1-8 and 10-24 above, and further in view of Dubensky et. al. (US20100173412A1, Pub. 07/08/2010; hereafter “Dubensky”.)
The Prior Art
The teachings of Beissert have been set forth supra. While Beissert teaches that the elements of the ORFs within the cis-replicon vector may be separated using such elements as 2A cleavage sites, Beissert fails to explicitly teach the use of HDV ribozyme sites for self-cleavage. However, the use of such sites, especially in alphavirus-based replicons, was known in the art, as evidenced by the teachings of Dubensky.
Dubensky teaches vectors for the delivery of heterologous nucleic acids, namely alphavirus replicons which utilize ribozymes (entire document; see abstract; ¶[0393]). Dubensky teaches the use of catalytic ribozyme processing sequences, such as those hepatitis delta virus ribozymes, and teaches the insertion of these cleavage sites at points in the alphavirus genome, such as between the 3’ polyA tail and transcription termination signals (¶[0393-0395]).
Given the teachings of Beissert, the generation of cis-replicon constructs would be known to a skilled artisan. Given the guidance from Beissert, different cleavage elements could be utilized in said alphavirus construct, such as the self-cleaving HDV ribozyme sequences noted by Dubensky. There would be a reasonable expectation of success in using these sites in replicons, given that Dubensky utilized these in alphavirus replicons to cleave off undesirable material. Therefore, arriving at the limitation of instant claim 9 would be obvious to a skilled artisan.
It would have been obvious to one of ordinary skill in the art to modify the methods and compositions taught by Beissert in order to utilize different cleavage techniques to separate polyproteins or fusion proteins. One would have been motivated to do so, given the suggestion by Dubensky that HDV self-cleavage ribozyme sites were useful for generating cleavage sites in alphavirus replicons. Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Conclusion
No claims are allowed.
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/RACHEL B GILL/
Primary Examiner, Art Unit 1671