DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s response filed 11/11/2025 has been received and considered entered. This is a response to amendments and arguments filed 11/11/2025.
Claims Status
Claims 1-2, 4-13, 15-22, 26-39, 43-48, 50-93, 96-97 is/are cancelled. Claims 98-99 are newly added. Claims 3, 14, 23-25, 40-42, 49, 94-95, 98-99 is/are currently pending. Claims 3, 14, 23-25, 40-42, 49, 94-95, 98-99 is/are under examination.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Enablement:
Claims 3, 14, 23-25, 40-42, 49, 94-95, 98-99 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 methods of expressing an expression system encoding a transactivator protein, a therapeutic protein, or an inhibitory RNA in cells in vitro and in the central nervous system of a mammal (including a human) in vivo by direct injection of a vector comprising the expression system into the central nervous system, does not reasonably provide enablement for methods of treating any disease in any subject, using a chimeric nucleic acid encoding any protein. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. This rejection is maintained.
The factors to be considered in determining whether a disclosure would require undue experimentation include:
A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01.
The breadth of the claims:
With respect to claim breadth, the standard under 35 U.S.C. §112, first paragraph, entails the determination of what the claims recite and what the claims mean as a whole. As such, the broadest reasonable interpretation of the claimed method is that it encompasses treatment of any disease in a mammal. Claim 42 narrows this breadth to treatment of a neurodegenerative disease or a disease caused by a protein deficiency or a genetic defect. A skilled artisan would not know how to use the method with a reasonable expectation of success based solely on what is disclosed in the specification.
The amount of direction provided by the inventor and the level of predictability in the art:
The specification teaches that the claimed method could treat symptoms of Huntington’s disease, spinocerebellar ataxia (paragraph [0054]), Fragile X ataxia syndrome, or Fragile X (paragraph [00109]). Paragraph [00134] teaches additional diseases which could be treated by the claimed method. However, these applications in treatment of diseases are presented as prophetic (see additionally paragraphs [00300]-[00317]). The art at the time of filing provides enabling guidance for two-cassette inducible gene regulation systems used in methods of treating specific diseases in mammals by expressing specific nucleic acids or proteins, such as in Vogel (2004) and Stieger (2009); the art at the time of filing also provided enabling guidance for using alternative splicing of a minigene to regulate expression of a transactivator protein in vivo in insects, not in a method of treating a disease (see US9970025B2, herein Alphey); however, the art at the time of filing does not provide enabling guidance for the use of minigenes which undergo alternative splicing as an inducible regulator of transgene expression in a method of treating a disease in a mammal. Furthermore, as taught by paragraphs [0096]-[00102] of the instant specification and by Alphey, minigenes which undergo alternative splicing and are derived from endogenous genes which undergo alternative splicing will interact with endogenous splicing modifiers in cells into which the minigenes are introduced, which would render unpredictable the level of control exerted by a small molecule splicing modifier on the regulation of minigene alternative splicing. The specification as filed does not provide guidance that overcomes this unpredictability within the art.
The existence of working examples:
What is enabled by the working examples is narrow in comparison to the breadth of the claims: The specification discloses in vitro methods of administering a two-cassette gene regulation system, wherein the target cells are immortalized cells (HEK293) (see Figs.5-16, 21; paragraphs [00312], [00314]-[00316]). HEK293 cells, being derived from human embryonic kidney cells, are materially distinct from neuronal cells, comprising different transcriptomes and proteomes, and thus cannot model the response of a neuronal disease to the administered compounds.
The quantity of experimentation needed to make or use the invention:
The standard of an enabling disclosure is not the ability to make and test if the invention works but one of the ability to make and use with a reasonable expectation of success. A patent is granted for a completed invention, not the general suggestion of an idea (MPEP 2164.03 and Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1325-26 (Fed. Cir. 2004). The instant specification is not enabling because one cannot follow the guidance presented therein, or within the art at the time of filing, and practice the claimed method without first making a substantial inventive contribution. Given that the nature of the invention is in vivo treatment of a disease in a mammal, a person having ordinary skill in the art would have to perform multiple further experiments, in animal models of a representative number of diseases and in human clinical trials, in order to demonstrate the invention could be used with a reasonable expectation of success. The amount of experimentation required for enabling guidance, commensurate in scope with what is claimed, goes beyond what is considered ‘routine' within the art, and constitutes undue further experimentation in order to use the method with a reasonable expectation of successfully treating any CNS disorder or neurodegenerative disease. Therefore, Claims 3, 14, 23-25, 40-42, 49, 94-95, 98-99 are rejected under 35 U.S.C. 112, first paragraph, for failing to meet the enablement requirement.
Response to Arguments
Applicant's arguments filed 11/11/2025 have been fully considered but they are not persuasive. In Applicant’s arguments, page 5 “B. Rejections Under 35 U.S.C. § 112(a), written description & enablement”, Applicant does not describe amendments to the claims which would overcome the enablement rejection—only the written description rejection, which has been withdrawn because of these amendments. Applicant also does not present an argument regarding the enablement rejection. The amendment to claim 1 specifying that the claimed method is a method of treating a disease in a human subject, as opposed to any mammal, does not overcome the enablement rejection, as the applicant is not enabled for any method of treating any disease, as discussed above. The enablement rejection is maintained.
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(s) 3, 23, 40, 49 is/are rejected under 35 U.S.C. 103 as being unpatentable over Paushkin (US 20110086833 A1), in view of Carette (2005) and Palacino (2015). This is a new rejection necessitated by amendments, relying on teachings from references applied in previously-presented rejections of now-cancelled claims.
Regarding claim 3, Paushkin teaches a method of expressing in vitro (paragraph [0021]) an expression cassette comprising a chimeric gene operably linked to an expression control element (paragraph [0264]), wherein this chimeric gene comprises a first and a second portion, and this first portion comprises a minigene and the second portion comprises a gene encoding a reporter protein, wherein the gene encoding the reporter protein lacks a start codon (claim 4). This minigene comprises exons 6, 7, and 8 of SMN pre-mRNA, wherein contacting the minigene with a small molecule splicing modifier (paragraph [0091]) causes alternative splicing of the minigene (claim 37), which splicing in turn controls expression of the chimeric protein (paragraph [0020]). Additionally, Paushkin teaches that the alternatively-spliced exon of the minigene (exon 7) comprises translation initiation regulatory sequences (SEQ ID NO:20; nucleotides 5960-6014 are exon 7, and this segment of the minigene comprises non-canonical eukaryotic translation initiation sequences, such as GTG, ATA, ATT, ATC; see Cao, 2021, which provides evidence that such non-canonical translation initiation sequences are known to exist in nature). Paushkin teaches that the second portion of the chimeric gene does not have a translation initiation sequence (claim 4). Paushkin further teaches that the expression of the protein is controlled by the alternative splicing of the exon that undergoes alternative splicing, and only in the presence of the small molecule splicing modifier is the protein encoded and expressed (Fig. 1; claim 37; paragraph [0091]). Paushkin also teaches that the structure of the expression cassette, from 5’ to 3’, comprises the minigene and the reporter gene (claim 1). Paushkin teaches that expression of the reporter protein is increased by inclusion of SMN2 exon 7 in the minigene, which inclusion is caused by contact with a splicing modifier compound (paragraph [0020]; claim 37). Paushkin teaches that the host cell containing the expression cassette (claim 11) can be a human cell (paragraph [0026]).
Regarding claim 23, Paushkin teaches that the expression cassette “may comprise one or more regulatory elements”, and these regulatory elements can be constitutive promoters, tissue-specific promoters, or inducible promoters (paragraph [0264]).
Regarding claim 40, Paushkin teaches that in order for a host cell to contain the expression cassette (claim 11), the host cell can be transformed by any known method for introducing polynucleotides into a host cell (paragraph [0277]).
Regarding claim 49, Paushkin teaches that for a host cell to contain the expression cassette, the host cell can be transformed by any known method for introducing polynucleotides into a cell (paragraph [0277]).
However, Paushkin does not teach that the encoded protein is a therapeutic protein.
Carette teaches a system for regulating gene expression, wherein alternative splicing of a minigene regulates downstream expression of a target protein.
Regarding claim 3, Carette teaches an expression cassette comprising a minigene and a downstream protein, wherein alternative splicing of the minigene controls expression of the downstream protein (Figure 1). While the working example of this downstream protein in Carette is a reporter gene (luciferase), Carette states that this reporter is used as a placeholder to demonstrate the effectiveness of this expression cassette, and that the expression cassette can be used to express a therapeutic protein in place of the reporter (page 1054 paragraph 2). Carette teaches that the expression cassette can be used to express a therapeutic protein, regulated by the alternative splicing of the upstream minigene, and that this therapeutic protein can be a pro-apoptotic protein, whose deficiency is a cause of some cancers and whose restored expression can be used to treat cancers (page 1054 paragraph 2).
Carette teaches a system for alternative splicing-regulated gene expression, by which the expression of a therapeutic protein may be controlled and used for the treatment of a disease. Paushkin teaches a similar system for alternative splicing-regulated gene expression, but does not disclose that such a system or similar systems could be used for the expression of a therapeutic protein. Although the minigenes and splicing modifiers used in Carette and Paushkin differ, the underlying concept—using the alternative splicing of a minigene to control expression of a downstream gene—is shared between the two. It therefore would have been obvious to a person of ordinary skill in the art at the time of filing that the expression of a therapeutic protein could be regulated by the alternative splicing of an upstream minigene, and that a minigene whose alternative splicing regulates the expression of a reporter gene, such as in Paushkin and Carette, could also regulate expression of a therapeutic protein, as described in Carette. Such a person would be motivated to apply the concepts of Carette to replace the reporter gene of Paushkin with a gene encoding a therapeutic protein in order to treat a subject to which the splicing modulator of Carette, and thus by extension the minigene of Carette, cannot be administered.
However, Paushkin and Carette do not teach that the alternate splicing of the SNM2 exon 7 minigene is modulated by the splicing modifier LMI070.
Palacino teaches that the compound LMI070 (also NVS-SM1) is an effective splice modifier of SMN2, as required by claim 3.
Regarding claim 3, Palacino teaches a small molecule drug LMI070 which enhances inclusion of exon 7 in the SMN protein (page 511 paragraph 4; Figure 1; Figure 2, showing that SMN exon 7 inclusion is increased positively correlated to increased doses of LMI070).
Paushkin does not teach the compound LMI070 as a splice modifier of SMN2 which increases inclusion of SMN2 exon 7, and does not disclose LMI070. Palacino does teach that LMI070 can increase inclusion of SMN2 exon 7. For the alternative splicing of the minigene of Paushkin to regulate the expression of the downstream gene, the splicing modifier must be capable of increasing inclusion of SMN2 exon 7. Therefore, although Paushkin does not disclose LMI070 as a splicing modifier, the evidence provided by Palacino for this compound’s functionality renders it obvious to a person of ordinary skill in the art at the time of filing that LMI070 is an alternative splicing modifier that can be applied to the invention of Paushkin, and could be used in cases where the difference in efficiency of LMI070 as compared to that of the compounds disclosed by Paushkin would be desirable.
Claim(s) 3, 23, 40-42, 49, and 94-95, 98-99 is/are rejected under 35 U.S.C. 103 as being unpatentable over Paushkin (US 20110086833 A1), and further in view of Palacino (2015), Vogel (2004), and Stieger (2009), and as evidenced by Cao (2021). This is a new rejection necessitated by amendments, relying on teachings from references applied in previously-presented rejections of now-cancelled claims.
Regarding claim 3, Paushkin teaches a method of expressing in vitro (paragraph [0021]) an expression cassette comprising a chimeric gene operably linked to an expression control element (paragraph [0264]), wherein this chimeric gene comprises a first and a second portion, and this first portion comprises a minigene and the second portion comprises a gene encoding a reporter protein, wherein the gene encoding the reporter protein lacks a start codon (claim 4). This minigene comprises exons 6, 7, and 8 of SMN pre-mRNA, wherein contacting the minigene with a small molecule splicing modifier (paragraph [0091]) causes alternative splicing of the minigene (claim 37), which splicing in turn controls expression of the chimeric protein (paragraph [0020]). Additionally, Paushkin teaches that the alternatively-spliced exon of the minigene (exon 7) comprises translation initiation regulatory sequences (SEQ ID NO:20; nucleotides 5960-6014 are exon 7, and this segment of the minigene comprises non-canonical eukaryotic translation initiation sequences, such as GTG, ATA, ATT, ATC; see Cao, 2021, which provides evidence that such non-canonical translation initiation sequences are known to exist in nature). Paushkin teaches that the second portion of the chimeric gene does not have a translation initiation sequence (claim 4). Paushkin further teaches that the expression of the protein is controlled by the alternative splicing of the exon that undergoes alternative splicing, and only in the presence of the small molecule splicing modifier is the protein encoded and expressed (Fig. 1; claim 37; paragraph [0091]). Paushkin also teaches that the structure of the expression cassette, from 5’ to 3’, comprises the minigene and the reporter gene (claim 1). Paushkin teaches that expression of the reporter protein is increased by inclusion of SMN2 exon 7 in the minigene, which inclusion is caused by contact with a splicing modifier compound (paragraph [0020]; claim 37). Paushkin teaches that the host cell containing the expression cassette (claim 11) can be a human cell (paragraph [0026]).
Regarding claim 23, Paushkin teaches that the expression cassette “may comprise one or more regulatory elements”, and these regulatory elements can be constitutive promoters, tissue-specific promoters, or inducible promoters (paragraph [0264]).
Regarding claim 40, Paushkin teaches that in order for a host cell to contain the expression cassette (claim 11), the host cell can be transformed by any known method for introducing polynucleotides into a host cell (paragraph [0277]).
Regarding claim 49, Paushkin teaches that for a host cell to contain the expression cassette, the host cell can be transformed by any known method for introducing polynucleotides into a cell (paragraph [0277]).
However, Paushkin does not teach that the alternate splicing of the SNM2 exon 7 minigene is modulated by the splicing modifier LMI070.
Palacino teaches that the compound LMI070 (also NVS-SM1) is an effective splice modifier of SMN2, as required by claim 3.
Regarding claim 3, Palacino teaches a small molecule drug LMI070 which enhances inclusion of exon 7 in the SMN protein (page 511 paragraph 4; Figure 1; Figure 2, showing that SMN exon 7 inclusion is increased positively correlated to increased doses of LMI070).
Paushkin does not teach the compound LMI070 as a splice modifier of SMN2 which increases inclusion of SMN2 exon 7, and does not disclose LMI070. Palacino does teach that LMI070 can increase inclusion of SMN2 exon 7. For the alternative splicing of the minigene of Paushkin to regulate the expression of the downstream gene, the splicing modifier must be capable of increasing inclusion of SMN2 exon 7. Therefore, although Paushkin does not disclose LMI070 as a splicing modifier, the evidence provided by Palacino for this compound’s functionality renders it obvious to a person of ordinary skill in the art at the time of filing that LMI070 is an alternative splicing modifier that can be applied to the invention of Paushkin, and could be used in cases where the difference in efficiency of LMI070 as compared to that of the compounds disclosed by Paushkin would be desirable.
Paushkin further fails to teach the following: a method for expressing a transactivator protein using the expression cassette; a second expression cassette, wherein the first expression cassette regulates expression of the second cassette, and wherein this second cassette comprises a therapeutic protein or an inhibitory RNA; an expression cassette wherein alternative splicing removes a stop codon in a minigene; linking the minigene to the gene with a cleavable peptide; the use of LMI070 as the splicing modifier; and the administration to the central nervous system of the expression cassette encapsulated in a viral vector.
However, Vogel teaches a system of two expression cassettes, wherein the first expression cassette regulates the second expression cassette through a mechanism controlled by a small molecule drug. Furthermore, Vogel teaches the administration of these expression cassettes to the central nervous system for the treatment of a neurodegenerative disease, wherein the expression cassettes are encapsulated in a viral vector.
Regarding claim 3, Vogel teaches a method for using a drug-inducible gene expression system for the expression of therapeutic nucleic acids. Vogel teaches that the first expression cassette in the inducible gene expression system comprises a transactivator protein, rTTA2-M2 (Figure 1). Vogel teaches that the drug-inducible gene expression system comprises two expression cassettes, wherein the transactivator protein encoded by the first expression cassette binds to the promoter region of the second expression cassette, and when activated by a drug, triggers expression of the transgene controlled by this promoter in the second expression cassette (Figure 1). Furthermore, Stieger teaches that such drug-inducible gene expression systems—wherein a first expression cassette encodes a transactivator that, when contacted with an activating drug, binds to a promoter in the second expression cassette and activates expression of a transgene—are commonly used in the art (Figure 1, showing generic schematics for different common variants of this gene expression regulation system). Vogel teaches that the RNA of the second expression cassette encodes a therapeutic protein (page 161). Vogel teaches that the therapeutic protein corrects a protein deficiency (deficiency of tyrosine hydroxylase) associated with a disease (restoration of tyrosine hydroxylase expression in deficient rat brains, treating the model of Parkinson’s disease, pages 161-162).
Regarding claims 40-41 and 94-95, Vogel teaches that both of the expression cassettes are encapsulated in a lentiviral vector (abstract) (required for claims 40-41 and 94-95).
Regarding claims 42, 98 and 99, Vogel teaches that the drug-inducible gene expression system is delivered to the central nervous system in a mammal in order to express a therapeutic protein associated with a neurodegenerative disorder (abstract).
Regarding claim 49, Vogel teaches that the first expression cassette contains a promoter compatible with use in nervous system tissues—a CMV promoter (Figure 1). Furthermore, Vogel teaches that the vector containing the expression cassettes is administered to the mammal by intrastriatal injection—i.e. administration to the brain, which forms part of the central nervous system (page 159 paragraph 4).
Vogel teaches a method for using a drug-inducible, two-expression-cassette gene expression regulatory system for the inducible or modulated expression of therapeutic nucleic acids in a model system of neurodegeneration. Vogel clearly shows that such mechanisms for drug-regulated therapeutic transgene expression, were well known to those of ordinary skill in the art at the time of filing. Stieger further provides evidence that many variants of this system were both well-known and commonly used in the art at the time of filing. However, the systems described in Vogel and Stieger are tetracycline-regulated systems, wherein the drug binds to and activates a transactivator protein, as compared to a system where the drug regulates expression of the transactivator. While the expression cassette of Paushkin does not encode a transactivator protein, it provides a mechanism for drug-regulated control of expression of a protein. To a person of ordinary skill in the art at the time of filing, it would be obvious that the reporter gene of Paushkin could be replaced with any gene whose expression one would be motivated to artificially regulate through administration of a drug; this would include replacing the reporter gene with a gene encoding a transactivator protein. The tet-regulated systems described in Vogel and Stieger are based on a concept of activating a transactivator through administration of a drug, and this active transactivator binds to and activates a promoter controlling expression of the desired transgene, wherein the transactivator and the desired transgene are encoded on separate expression cassettes. To a person of ordinary skill in the art at the time of filing, it would be obvious that alternative methods for producing an active transactivator would suffice to regulate expression of the desired transgene—and such alternative methods would include drug-mediated regulation of transactivator expression. This would be particularly salient to a person motivated to develop a drug-regulated gene expression system for use in subjects that cannot be administered tetracycline or tetracycline analogs, as would be required for tetracycline-regulated gene expression systems such as in Vogel and Stieger.
Furthermore, Vogel shows that drug-inducible gene expression systems utilizing two expression cassettes can be effectively used in the central nervous system and delivered via viral vectors. Paushkin teaches that the alternative splicing-regulated gene expression system can be introduced into a cell through any known means of transforming cells, but does not provide examples of transformation methods or host cells. Given the administration methods in Vogel, it would have been obvious to a person of ordinary skill in the art at the time of filing that drug-regulated gene expression cassettes could be effectively delivered to the central nervous system through viral vectors injected into structures of the central nervous system and through the use of appropriate promoters. Such a person would be motivated to apply the administration methods of Vogel to constructs analogous to those of Vogel or Paushkin if the goal were to express these drug-regulated gene expression systems in the central nervous system.
Claim(s) 14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Paushkin (US 20110086833 A1), Palacino (2015), Vogel (2004), and Stieger (2009), as applied to claims 3, 9, and 12 above, and further in view of Drouet (2009). This is a new rejection necessitated by amendments, relying on teachings from references applied in previously-presented rejections of now-cancelled claims.
The teachings of Paushkin, Palacino, Stieger, and Vogel are discussed above and can be combined to render obvious claims 3, 9, and 12. However, Paushkin, Palacino, Stieger, and Vogel do not teach an inducible expression system wherein expression of an inhibitory RNA is controlled.
Drouet teaches a tet-regulated gene expression system, exemplary of the tet-regulated systems described in Stieger, which regulates expression of an shRNA used to knock down expression of a protein.
Regarding claim 14, Drouet teaches a tet-regulated gene expression system, wherein a tet-activated transactivator regulates expression of an shRNA targeted to the HTT gene (page 278). Drouet teaches that conditional knockdown of the HTT gene through use of the tet-regulated gene knockdown system results in reduction of a marker of disease progression (reduction of DARPP-32, a marker of Huntington’s disease) (Figure 4).
Drouet, like Vogel, teaches a drug-regulated gene expression system comprising a first expression cassette encoding a transactivator protein, and a second expression cassette comprising the nucleic acid sequence of interest, whose expression is controlled by this transactivator. Both gene expression regulation systems are exemplary of the generic schemas described by Stieger as being commonly known and used in the art. However, while Vogel teaches the use of such a system to express a therapeutic protein, Drouet teaches the use of such a system to express an inhibitory RNA, specifically an shRNA, in order to knockdown a disease-associated gene for the treatment of the associated disease. It would have been obvious to a person of ordinary skill in the art at the time of filing that a gene expression system that can be used to regulate expression of a protein, such as in Paushkin and Vogel, could be used to regulate expression of an inhibitory RNA, such as in Drouet. Such a person would be motivated to apply the inhibitory RNA expression cassette structure of Drouet to the gene expression regulatory structures of Paushkin or Vogel in order to decrease expression of a pathogenic protein.
Claim(s) 24-25 is/are rejected under 35 U.S.C. 103 as being unpatentable over Paushkin (US 20110086833 A1), Palacino (2015), and Carette (2005), as applied to claim 3 above, and further in view of Takata (2011) and Nelson and Cox (2013). This is a new rejection necessitated by amendments, relying on teachings from references applied in previously-presented rejections of now-cancelled claims.
The teachings of Paushkin, Palacino, and Carette are discussed above and can be combined to render obvious claim 3. However, Paushkin, Palacino, and Carette do not teach a construct wherein multiple genes in an expression cassette are linked by sequences encoding self-cleaving peptide linkers.
Takata teaches a construct wherein multiple genes in an expression cassette are linked by sequences encoding self-cleaving peptide linkers.
Regarding claim 24-25, Takata teaches a gene expression cassette wherein multiple genes are linked by sequences encoding self-cleaving peptide linkers (required for claims 24-25) (Figure 1).
The expression cassettes of Paushkin and Carette encode fusion proteins comprising the translated, alternatively-spliced minigenes and the reporter or therapeutic protein. However, they do not teach a mechanism for cleaving the translated minigene from the protein: the fusion proteins of Paushkin and Carette retain significant or total function relative to the wild-type reporter protein, and therefore cleaving the translated minigene from the reporter is not necessary for the purposes of Paushkin and Carette. However, it is known in the art that the overall amino acid sequence of a protein determines the tertiary and quaternary structures of the protein, which in turn determine the activity of the protein (Nelson and Cox, pages 31, 97, 133, 143-144). Accordingly, the fusion of two amino acid sequences can alter the activity of the fused proteins, which can result in reduced activity compared to the separate component proteins (Nelson and Cox, pages 325-327). It would therefore be obvious to a person of ordinary skill in the art, motivated to regulate expression of a functional transactivator through alternative splicing of a fused minigene, that in order to ensure full activity of the transactivator protein compared to its wild-type counterpart, the transactivator and translated minigene would need to be cleaved—and Takata provides a mechanism by which fused proteins may be cleaved, through the insertion of sequences encoding self-cleaving peptide linkers.
Response to Arguments – 35 U.S.C. 103
Applicant's arguments filed 11/11/2025 have been fully considered but they are not persuasive. Applicant has not presented arguments regarding the previously-presented rejections of claims under 35 USC 103. Applicant’s arguments assert that the incorporation of limitations of cancelled claims into independent claim 3 overcome the previous rejections. However, as discussed above, claim 3 remains rejected under 35 USC 103 over the references applied in the previous 35 USC 103 rejections.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 3, 14, 23-24, 40-41, 94-95 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6, 7, 41, 45-46, 49-51, 53-54, and 57 of copending Application No. 17/798,851 (reference application), in view of Paushkin (US 20110086833 A1). This rejection is maintained.
Claims 1, 6-7, 41, 45-46, 49-51, 53-54, and 57 of ~851 recite all of the required limitations of claims 3, 14, 23-24, 40-41, 94-95 of the instant application except that the encoded gene operably linked to the alternatively spliced minigene lacks translation initiation regulatory sequences, as required by instant claim 3. Furthermore, the “splicing modifier drug” of copending claim 54 is defined in the copending specification as encompassing drugs such as LMI070 (paragraphs [0026], [00101]), and wherein copending SEQ ID NO:1 is an SMN2 exon 7 minigene.
Paushkin teaches a nucleic acid comprising an alternatively spliced minigene (comprising an alternatively spliced exon) joined to a chimeric protein-encoding sequence, wherein the expression of the chimeric protein is regulated by the alternative splicing of the minigene, and wherein the sequence encoding the chimeric protein does not comprise translation initiation regulatory sequences.
Regarding claim 3, Paushkin teaches that the sequence encoding the chimeric protein does not comprise translation initiation regulatory sequences (claim 4).
Both ~851 and Paushkin disclose gene expression regulatory systems wherein the alternative splicing of a minigene, controlled by a small molecule splicing modifier, regulates expression of a downstream-encoded protein. ~851 does not recite a limitation that the protein-coding sequence does not comprise a translation initiation sequence. However, Paushkin teaches precisely this. The removal of translation initiation sequences in the protein-coding sequence necessitates that the alternative splicing of the upstream minigene result in the inclusion of a translation initiation sequence, else the protein will not be expressed. Because ~851 does not recite that the protein-coding sequence comprises or lacks a translation initiation sequence, the sequence as recited can comprise a translation initiation sequence, which could result in some degree of protein expression independent of splicing of the upstream minigene. It would be obvious to a person of ordinary skill in the art to combine the teaching of Paushkin that the protein-coding sequence lacks a translation initiation sequence with the recited composition of ~851, as this combination would ensure the complete dependence of the expression of the protein on the alternative splicing of the upstream minigene and by extension, on the administration of the small molecule splicing modifier.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant's arguments filed 11/11/2025 have been fully considered but they are not persuasive. Applicant’s sole argument is that “[i]f a provisional nonstatutory double patenting rejection is the only rejection remaining in an application having the earlier patent term filing date, the examiner should withdraw the rejection in the application having the earlier patent term filing date and permit that application to issue as a patent.” (page 6) As the provisional nonstatutory double patenting rejection is not the only rejection remaining in the instant application, the pending provisional nonstatutory double patenting rejection is maintained.
Conclusion
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.
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/AFRICA M MCLEOD/ Examiner, Art Unit 1635
/KIMBERLY CHONG/ Primary Examiner, Art Unit 1636