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 .
Applicant’s amendments and arguments of December 9, 2025, are entered.
Claims 5, 7, and 9 have been amended.
Claims 8, 13, and 39 have been canceled.
No new claims have been added.
Double Patenting
The double patenting objections to claim 10 if 1 is allowed and claim 40 if claim 26 is found allowable is being maintained.
A rejection based on double patenting of the “same invention” type finds its support in the language of 35 U.S.C. 101 which states that “whoever invents or discovers any new and useful process... may obtain a patent therefor...” (Emphasis added). Thus, the term “same invention,” in this context, means an invention drawn to identical subject matter. See Miller v. Eagle Mfg. Co., 151 U.S. 186 (1894); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Ockert, 245 F.2d 467, 114 USPQ 330 (CCPA 1957).
A statutory type (35 U.S.C. 101) double patenting rejection can be overcome by canceling or amending the claims that are directed to the same invention so they are no longer coextensive in scope. The filing of a terminal disclaimer cannot overcome a double patenting rejection based upon 35 U.S.C. 101.
Applicant is advised that should claim 1 be found allowable, claim 10 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m). Claim 10 is merely restating the same composite cell line structure found in claim 1. Thus, despite a slight difference in wording, these claims have substantially the same scope.
Applicant is advised that should claim 26 be found allowable, claim 40 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m). Claim 26 is directed to a method for producing defective interfering particles, and claim 40 is directed to a population of such particles by the method of claim 26. The particles in claim 40 are structurally the same particles generated by the method of 26. Thus, despite the difference in wording, these claims have substantially the same scope.
Response to Argument
Examiner notes the only request by applicant is that the “provisional rejection be held in abeyance until allowable subject matter is agreed upon” [Remarks, Double Patenting, ¶ 2]. However, the statement does not substantively address the reason for the objection, and therefore the objection is being maintained.
Claim Rejections - 35 USC § 112(a)
The §112(a) enablement rejection for claims 1, 4-7, 9-11, 14-16, 18, 20, 22, 29, 30, 34, as well as claims 26 and 40 is being maintained.
The §112(a) enablement rejection for claims 8 and 13 is withdrawn given Applicant canceled these claims.
Claims 1, 4-7, 9-11, 14-16, 18, 20, 22, 29, 30, 34, and Claims 26 and 40 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The nature of the invention:
The invention is in the nature of constructing a multi-vector system for defective interfering particle production using viruses from the Flaviviridae family.
Breadth of claims:
The claims encompass all Flaviviridae structural proteins, non-structural proteins, and defective interfering genomic sequences for producing defective interfering particles. This includes hundreds of viruses, including but not limited to dengue virus serotypes as stated in Applicant’s specification, but also West Nile virus, Zika virus, Yellow Fever virus, Japanese encephalitis virus, tick-born encephalitis, Kunjin virus, as well as others. Applicant’s specification includes over 50 different types of Flaviviridae family viruses.
The amount of direction or guidance present in the Application:
Applicant’s disclosure asserts “…inventors have developed virus interfering particles (DIPs)” pertaining to Dengue virus interfering particles and methods for producing such particles in vitro. Additionally, Applicant’s specification goes on to state that the Flavivirus can be selected from a group of viruses that include over 50 different species. However, Applicant’s specification only provides examples where Dengue virus was used. Starting on pg. 3 of the specification, Applicant describes Dengue virus serotypes 1-4 with each serotype respective GenBank accession number. Other examples include the use of Dengue virus non-structural proteins NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5 [pg. 4 Ln. 23-24]. No analogous guidance is provided for any other Flaviviridae member other than a generic statement that those specific viruses can be used. There is no guidance or description about what non-structural proteins or structural proteins can be used. Furthermore, there is no mention of corresponding defective interfering genomic sequences that can be used.
Presence of working examples:
The specification only provides examples for the Dengue virus and its serotypes that include the structural and non-structural proteins. This is further supported by the tables provided in Applicant’s specification. Table 1 lists the structural protein expression of the serotype 2 Dengue virus. Table 2 lists examples of Dengue virus non-structural protein expression. Table 3 lists Dengue virus serotype 2 defective interfering RNA expression. Table 4 lists Dengue virus where the open reading frame is either monkey codon optimized or human codon optimized and is the same thing for Table 5.
The relative skill in the art:
An ordinary artisan in the area of molecular virology and vector engineering would typically have several years’ experience in the field where the artisan would have gained considerable hand-on experience with reverse genetics, cell cultures, and viral replication assays. Additionally, the Art itself is a recognition of what is understood by the Artisan, and thus, does not make the breadth of the claim more predictable.
The predictability or lack thereof in the art:
Applicant’s specification lists over 50 different viruses that fall within the Flaviviridae family. Additionally, the Flaviviridae family includes over 100 recognized viruses that include 4 different genera including Flavivirus, Pestivirus, Hepacivirus, and Pegivirus. There are also viruses that are known but have not been classified known as Orthoflaviviruses [https://en.wikipedia.org/wiki/Flaviviridae]. Additionally, production of defective interfering particles typically requires the use of a helper virus that provides all of the viral enzymes, co-factors, and RNA packaging mechanisms allowing the defective interfering RNA to replicate and assemble in into defective interfering particles that are subsequently secreted by infected cells [Bdeir et al., “A system for production of defective interfering particles in the absence of infectious influenza A virus” PLOS one, 2019]. One of the main obstacles in producing isolated defective interfering particles is that the helper virus causes contamination and is impractical to remove [Li et al., “Dengue virus-free defective interfering particles have potent and broad anti-dengue virus activity” Nature Communications Biology, 2021]. However, there is no existing art that would teach a skilled Artisan the specific configurations and combinations of structural proteins, non-structural proteins, and defective interfering genome sequences that are listed in Applicant’s specification alone. This is especially true given that the current claimed invention lacks helper viruses [Pg. 2 Summary of the Disclosure]. Given the above and that Applicant has only provided examples for the Dengue virus and the lack of existing art, it would be difficult for an Artisan to quantify the number of combinations that would make up the trivector product-by-process described by Applicant.
The quantity of experimentation needed:
Given:
The number of viruses found within the Flavivirdae family,
The possible number of different structural and non-structural proteins associated with each species found within the Flaviviridae family,
The need to determine optimal cell lines and culture conditions for each type of virus, and
Designing defective interfering sequences that generate competent interfering particles for each virus and combinations thereof.
The Artisan would have to experiment on an untold number of virus species and combinations would be great. Given this, the level of experimentation is considered undue, as it would require experimentations on over 50 different virus species and combinations thereof for determining ideal combinations related to structural and non-structural proteins, as well as defective interfering genomic sequences.
Conclusion:
Based on the above Wands analysis, a person of ordinary skill would be required to undertake undue experimentation to make and use the full scope of the claimed invention, i.e. producing defective interfering particles for every virus within the Flaviviridae family. The specifications working examples only include those of the Dengue virus and its serotypes. Therefore, claims 1, 4-11, 13-16, 18, 20, 22, 29, 30, 34 are not enabled.
Response to Argument
Applicant argues, that although Dengue virus is exemplified, the specification provides general structural and functional requirements for Flaviviridae proteins, specifically C, prM/M, E; NS1-NS5, along with sequence references and GenBank accession numbers for multiple species and guidance on codon optimization for mammalian expression and DIP assembly. Applicant also argues that the disclosure further teaches codon optimization, promoter selection, and vector design strategies that are not virus-specific, and therefore are enabling for adaptation to other Flaviviridae members without undue experimentation.
The examiner finds this argument unpersuasive.
The claims are generically directed to a cell line capable of producing defective interfering particles for any virus within the Flaviviridae family. However, the specification provides working examples and structural guidance limited to flavivirus embodiments, and more specifically Dengue virus embodiments including constructs containing C, prM/M E, and NS1-NS5 proteins, along with Dengue-derived defective interfering genomic sequences. The disclosure does not provide representative examples, structural constructs, or defective interfering genomic designs for other genera within Flaviviridae, including Hepacivirus, Pegivirus, or Pestivirus.
The International Committee on Taxonomy of Viruses report for Hepacivirus that members of this genus possess materially different genome organization and protein architecture, including polyprotein processed into Core, E1, E2, p7, NS2, NS3, NS4B, NS4A, NS5A, and NS5B. They also lack the prM/M and NS1 protein characteristics of flaviviruses. Additionally, Pegivirus and Pestivirus members exhibit distinct structural proteins, cleavage patterns, and replication complex organization. These differences vary considerably from flaviviruses. The specification does not teach how to adapt the disclosed flavivirus-based CprME structural expression systems or dengue-derived defective interfering genomic constructs to viruses lacking those structural components or possessing different assembly pathways [Family: Flaviviridae, Chapter Version: ICTV Ninth Report; 2009 Taxonomy Release].
Furthermore, viruses like jingmenviruses, which are currently classified as Flaviviridae as unclassified, have segmented genomes containing four to five RNA segments encoding multiple structural and non-structural proteins that only partially resemble flaviviral proteins, e.g. NS2B,NS3, and NS5, do not possess the singly polyprotein organization found in flavivirus species [Colmant et al., Jingmenviruses: ubiquitous, understudied, segmented flavi-like viruses, Frontiers in Microbiology, 2022]. Given the substantial structural and functional diversity within the claimed family and the absence of representation of embodiments outside flavivirus genus, a person of ordinary skill would have to engage in undue experimentation to determine whether and how defective interfering particles could be produced for Hepacivirus, Pegivirus, or Pestivirus, not to mention other genera such as Jingmenviruses. Based on this, the §112(a) enablement rejection for claims 1, 4-7, 9-11, 14-16, 18, 20, 22, 29, 30, 34, as well as claims 26 and 40 is being maintained.
Examiner finds Applicant’s argument directed to §112(a) written description rejection for claim 14 persuasive. Therefore, the rejection for claim 14 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 rejection requirement where the claims contained 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 inventors, at the time the application was filed, had possession of the claimed invention, is withdrawn.
With respect to claim 34, the rejection for claim 34 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 rejection requirement where the claims contained 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 inventors, at the time the application was filed, had possession of the claimed invention, is being maintained.
Claim 34 uses the generic phrase “treating or preventing a Flaviviridae disease in a subject reducing the load of a Flavivirus RNA in a subject” with respect to producing defective interfering particles using a trivector method inserted into a host cell for replication.
The specification provides antecedent basis for “treating or preventing a Flaviviridae disease in a subject reducing the load of a Flavivirus RNA in a subject” with respect to the use of defective interfering particles derived from Flavivirus, i.e. Dengue virus, capable of inhibiting replication of Dengue virus serotypes 1-4 [Fig. 8, pg. 16 Ln. 20].
Applicant’s specification defines Flaviviridae disease as “…a disease in a host caused by a Flaviviridae virus as described herein” [pg. 25 Ln. 6]. The definition goes onto list numerous symptoms associated with various infections caused by a Flaviviridae disease, e.g. fever, myalgia, abortion, myocardial necrosis, encephalitis etc [Id.]. The specification goes onto describe “treating” and “preventing” as both inhibiting viral replication and alleviating of one or more symptoms associated with the disease or condition [Pg. 23 Ln. 8-29]. However, the specification is only claiming to alleviate or prevent symptoms in a generic way, e.g. fever, rash, myalgia, hemorrhagic fever, encephalitis, etc. [pg. 25 Ln. 6]. However, this list does not include congenital conditions that are a result of the infection and are considered part of the disease or chronic conditions such as chronic hepatitis C associated with certain Flaviviridae viruses. For example, Hepatitis C virus is a member of the virus family Flaviviridae and is the most common cause of cirrhosis in various countries [See Zaltron et al., “Chronic HCV infection: epidemiological and clinical relevance” BMC Infect Dis. 2012]. It is also associated with a host of alterations to the host immune system that can result in immunological abnormalities and even autoimmune disease, e.g. rheumatoid factor production [Natural history and clinical impact ¶ 9]. Another issue of chronic hepatitis C is fibrosis of the liver which leads to distortion of hepatic architecture and impairment of liver microcirculation and cell functions [Id. ¶ 2]. Another example is Japanese encephalitis which causes meningeal symptoms such as severe headaches and where there is no specific treatment currently available other than treating the specific symptoms that are presented in patients [Health Care Providers “Treatment and Prevention of Japanese Encephalitis”, 2024]. Lastly, the claim attempts to generically cover treatment and prevention of all diseases caused by any virus within the Flaviviridae family using defective interfering particles. The Flaviviridae family includes 4 different genera made up of Flavivirus, Hepacivirus, Pegivirus, and Pestivirus. These genera contain dozens of distinct viral species that are associated with a wide range of disease across both human and animal populations. Furthermore, the phrase “treating and preventing” include prophylactic, acute, and chronic therapeutic use. Because of this, a person of ordinary skill would be unable to quantify this information, let alone be able to determine what combination of Flavivirus species would work across both human and non-human animals.
Given the generic scope of “treating or preventing a Flaviviridae disease in a subject reducing the load of a Flavivirus RNA in a subject”, and the absence of teaching what other disease can be prevented and/or treated aside from the examples of Dengue viral infection provided in Applicant’s specification, an Artisan would not understand Applicant to be in possession of the generic scope of “treating or preventing a Flaviviridae disease in a subject reducing the load of a Flavivirus RNA in a subject”.
Response to Argument
Applicant argues the present system utilizes a stable cell line that produces all of the DENV structural and non-structural proteins in the absence of live The structural and non-structural proteins are encoded by two separate non-overlapping codon optimized mRNAs, so that the probability of forming recombinant virus is low and inventions DENV RNA cannot be made. The present inventors were the first to identify that optimized DENV open reading frames outperformed natural sequences in the current system. As such the DIP(s) of the present invention engineered to contain specific deletion that optimize their antiviral effects. The results that DIPs of the present invention have high specificity, broad anti-viral activity against a range of viruses and serotypes and the ability to block or attenuate virus transmission. For example, in vitro studies demonstrate the DIPs of the present invention inhibit the replication of all four virus serotypes (DENV1-4) with significant fold reductions (see, Figure 8), as replication in Huh7 cells 9up to 39-fold reduction (see, Example 16). well as Zika virus Accordingly, these DIPs are clearly suitable for the treatment and/or prevention of Flaviviridae, reducing the viral load of Flaviviridae and can be useful for reducing the transmission of Flaviviridae between a host and a carrier.
The examiner finds this argument unpersuasive.
The claim scope encompasses disease caused by any member of the Flaviviridae family, reducing the load of a Flavivirus RNA in a subject, or reducing the transmission of a Flaviviridae virus between a host and a carrier by administering defective interfering particles. However, the specification only provides support limited to Dengue-derived defective interfering particles. This includes optimized constructs based on Dengue virus with in vitro data showing inhibition of dengue serotypes and activity against Zika virus. The specification does not describe or disclose defective interfering particles derived from or effective against other genera found in the Flaviviridae family, e.g. Hepacivirus, Pegivirus, or Pestivirus, or even other genera such as Jingmenviruses. The specification provides no representative sequences, structural features, or data to support treatment or transmission reduction for those viruses falling with the above-mentioned viruses. Because of this, the §112(a) written rejection for claim 34 is maintained.
Claim Rejections - 35 USC § 112(b)
In light of the amendment, the rejection for claims 5, 7, and 9 being rejected under 35 U.S.C. 112(b) or 35 U.S.C. (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 are withdrawn.
Claim 20 being 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 is being maintained.
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 20 recites the broad recitation “comprises about 155
nucleotides to about 1000 nucleotides, and the claim also recites “preferably between about 200
nucleotides to about 500 nucleotides” which is the narrower statement of the range/limitation.
The claim(s) are 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.
Response to Argument
Examiner notes that Applicant’s response to the Non-Final Office Action on December 9, 2025, did not address the maintained rejection for Claim 20.
Claim Rejections - 35 USC § 112(d)
In light of the amendments cancelling claims 8 and 13, the rejection for claims 8 and 13 for being 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 are withdrawn.
Claim Rejections - 35 USC § 102
In light of the amendments canceling claim 39, the rejections for claim 39 under 35 U.S.C. §102(a)(1) as being anticipated by GenBank [Accession No. HM016523.1, 2010], is withdrawn.
Conclusion
No claims allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOHN DAVID MOORE whose telephone number is (703)756-1887. The examiner can normally be reached M-F 8-5.
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 by telephone are unsuccessful, the examiner’s supervisor, Tracy Vivlemore can be reached at 571-272-2914. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JOHN DAVID MOORE/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638