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 .
DETAILED ACTION
This Office Action is a response to Applicant’s Election filed August 6, 2026.
Claims 1-29 are pending in the instant application.
Election/Restrictions
Applicant’s election of Group I (without traverse) in the reply filed on August 6, 2026 is acknowledged. Applicants’ further species election (without traverse) of lentiviral vector and the Es promoter in the reply filed on August 6, 2026 is also acknowledged.
Claims 7 and 16-29 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention there being no allowable generic or linking claim. Applicant timely made the restriction (election) requirement in the reply filed on August 6, 2026.
The requirement is still deemed proper and is therefore made FINAL.
Accordingly, claims 1-6 and 8-15 have been examined on the merits as detailed below:
Information Disclosure Statement
It is noted that Applicants have not filed an information disclosure statement under § 1.97(c). Applicant is reminded of 37 CFR § 1.56, which details Applicants duty to disclose all information known to be material to patentability.
Drawings
The Drawings filed on July 21, 2023 are acknowledged and have been accepted by the Examiner.
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.
Claims 1-6 and 8-15 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
The following quotation from section 2163 of the Manual of Patent Examination Procedure is a brief discussion of what is required in a specification to satisfy the 35 U.S.C. 112 written description requirement for a generic claim covering several distinct inventions:
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice..., reduction to drawings..., or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus... See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
Thus, when a claim covers a genus of inventions, the disclosure must provide written support for the entire scope of the genus. Support for a genus is generally found where the Applicant has provided a number of examples sufficient so that one in the art would recognize from the specification the scope of what is being claimed and that applicant was in possession of the claimed genus.
The claims are drawn to a dual-cassette vector comprising a. a first transcription unit (TU) comprising a first promoter, a first nucleic acid sequence, and a first termination sequence; b. a second transcription unit (TU) downstream from said first TU; said second TU comprising a second promoter, a second nucleic acid sequence, and a second termination sequence; and c. a cytomegalovirus (CMV) core fragment (cC element). The present Specification discloses that, “dual-cassette” comprises two transcription units (TUs).
There is insufficient written description for the first promoter; second promoter; and cC element encompassed by the claims. The present Specification is explicit in disclosing:
In this study, use of the small-size 120 bp cC element, in cooperation with the short but weak Es (212 bp; GenBank Accession No. J04617.1, nucleotides 397 to 608) and SV40 promoter (Sv) (269 bp; GenBank Accession No. MT086573.1, nucleotides 4403 to 4671), for modulating transcription interference between two TUs in dual-cassette LVs
The Specification does not describe any other first or second promoter sequences or any cC elements with any percentage identity to SEQ ID NO: 1 that functions as a dual-cassette vector to drive transgene expression in transduced cells. Only nucleotides 397 to 608 of GenBank Accession No. J04617.1; nucleotides 4403 to 4671 of GenBank Accession No. MT086573.1; and the cC element (50 bp to +70 bp) (SEQ ID NO: 1 of the present invention) are described.
Concerning the cC element, written description requirement for claims that recite, “wherein said cC element comprises at least 75%,or at least 80%, or at least 85%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99% sequence identity to TAGGCGTAGT CGGTGGGAGG TCTATATAAG CAGAGCTCGT TTAGTGAACC GTCAGATCGC CTGGAGACGC CATCCACGCT GT TTTGACCT CCATAGAAGA CACCGGGACC GATCCAGCCT (SEQ ID NO: 1)” is not met because the Specification does not provide any description of any variants or what sequences could be modified (added, deleted or mutated) that retain promoter function. Accordingly, the claims encompass using a genus of cC element sequence which is not adequately described. Therefore, the claims are rejected because there is insufficient description of the genus of the cC element encompassed by the claims.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116). It is noted that conception is not achieved until reduction to practice has occurred regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
To satisfy the written description requirement an applicant must describe the invention is such a way as to convey to one skilled in the art that applicant had the invention in his possession when the application was filed. Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc). In cases such as the instant application where a genus is claimed, the specification must contain “either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Id. at 1350. However, written description requirement for claims that require any first promoter; any second promoter; and any cC element is not met.
The entire genus of dual-cassette vector comprising a. a first transcription unit (TU) comprising a first promoter, a first nucleic acid sequence, and a first termination sequence; b. a second transcription unit (TU) downstream from said first TU; said second TU comprising a second promoter, a second nucleic acid sequence, and a second termination sequence; and c. a cytomegalovirus (CMV) core fragment (cC element) does not exist in the instant application. That is, adequate written description support does not exist to practice the full scope of the invention claimed. Only a dual-cassette vector comprising the small-size 120 bp cC element (50 bp to +70 bp) (SEQ ID NO: 1 of the present invention), in cooperation with the short Es (212 bp; GenBank Accession No. J04617.1 (human elongation factor-1 alpha (EF-1α) promoter), nucleotides 397 to 608) and SV40 promoter (Sv) (269 bp; GenBank Accession No. MT086573.1, nucleotides 4403 to 4671) meet the written description requirement. The specification nor the art discloses neither a representative number of species vectors nor any structure/function correlation that would enable one of skill to immediately envision the genus of dual-cassette vectors required to practice the full scope of the invention.
As stated above, the MPEP states that written description for a genus can be achieved by a representative number of species within a broad generic claim. Given the breadth of the claims, the Specification lacks sufficient variety of species to reflect the variance in the genus.
In conclusion, the Specification and the prior art as filed does not provide sufficient descriptive support for the myriad of dual-cassette vectors embraced by the claims. For the reasons discussed above, the 35 USC § 112 rejection for written description is applicable.
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Claims 1-6 and 8-15 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. This is an enablement rejection.
There are many factors to be considered when determining whether there is sufficient evidence to support determination that a disclosure does not satisfy the enablement requirements and whether any necessary experimentation is undue. These factors have been described by the court in In re Wands, 8 USPQ2d 1400 (CA FC 1988). Wands states at page 1404,
“Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman. They include:
(1) the quantity of experimentation necessary,
(2) the amount of direction or guidance presented,
(3) the presence or absence of working examples,
(4) the nature of the invention,
(5) the state of the prior art,
(6) the relative skill of those in the art,
(7) the predictability or unpredictability of the art, and
(8) the breadth of the claims.”
The nature of the invention and the breadth of the claims:
The claims are drawn to a dual-cassette vector comprising a. a first transcription unit (TU) comprising a first promoter, a first nucleic acid sequence, and a first termination sequence; b. a second transcription unit (TU) downstream from said first TU; said second TU comprising a second promoter, a second nucleic acid sequence, and a second termination sequence; and c. a cytomegalovirus (CMV) core fragment (cC element).
The amount of direction or guidance and presence/absence of working examples:
The present invention provides examples wherein the use of the small-size 120 bp cC element (50 bp to +70 bp) (SEQ ID NO: 1 of the present invention), in cooperation with the short but weak Es (212 bp; GenBank Accession No. J04617.1 (human elongation factor-1 alpha (EF-1α) promoter), nucleotides 397 to 608) and SV40 promoter (Sv) (269 bp; GenBank Accession No. MT086573.1, nucleotides 4403 to 4671), for modulating transcription interference between two TUs in dual-cassette LVs. The present Specification discloses that, “dual-cassette” comprises two transcription units (TUs). The claims are so broad to recite any first promoter; any second promoter; and any cC element. However, only specific regions of the Es and Sv promoters and a specific core fragment (cC element) have been shown to drive transgene expression in transduced cells.
The state of the prior art and the predictability or unpredictability of the art:
The claimed invention is a class of invention which the CAFC has characterized as “the unpredictable arts such as chemistry and biology.” Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
The Specification teaches unpredictability in the strength of promoters in dual-cassette vectors. For example, the Disclosure teaches that promoter interference between adjacent TUs may occur and often results in reduced expression or even complete suppression of genes in one or both genes. Applicant’s results show strength- and position-dependent interference (suppression) between Es- and cC-driven TUs and indicate a position-dependent enhancer activity of cC element to “dismal” Es promoter.
The art of Boateng-Antwi et al. (J Gene Med. 2021;23:e3380, pages 1-15) teaches the relative positioning and the strength of promoters affect expression interference in dual cassette vectors. For example, Boateng-Antwi et al. teach several factors may contribute to the interference, including the comparative strengths and the relative positioning of the promoters, susceptibility of promoter(s) to epigenetic modification and the roles of other cis-acting regulatory elements. Also, the prior art of Curtin et al. (Gene Therapy (2008) 15, 384-390) teach promoter interference between two internal heterologous promotors in a late-generation lentiviral vector, and the interference between human cytomegalovirus-immediate-early promoter and human elongation-factor-1α promoter occurred bidirectionally with both promoters markedly impairing expression of the adjacent transcription unit.
The level of skill in the art:
The relative skill of those in the art is considered to be high, being a graduate student or post-doctoral fellow in a biological science.
The quantity of experimentation necessary:
A review of the instant application finds an example wherein the use of the small-size 120 bp cC element (50 bp to +70 bp) (SEQ ID NO: 1 of the present invention), in cooperation with the short Es (212 bp; GenBank Accession No. J04617.1, nucleotides 397 to 608) and SV40 promoter (Sv) (269 bp; GenBank Accession No. MT086573.1, nucleotides 4403 to 4671), for modulating transcription interference between two TUs in dual-cassette LVs to drive transgene expression in transduced cells. Based on studies of the present invention and the art of Boateng-Antwi et al., relative positioning and strength of promoters affect expression interference in dual-cassette vector. See also, Curtin et al.
Neither the Specification nor the art teach a dual-cassette vector comprising a. a first transcription unit (TU) comprising a first promoter, a first nucleic acid sequence, and a first termination sequence; b. a second transcription unit (TU) downstream from said first TU; said second TU comprising a second promoter, a second nucleic acid sequence, and a second termination sequence; and c. a cytomegalovirus (CMV) core fragment (cC element) other than the use of the small-size 120 bp cC element (50 bp to +70 bp) (SEQ ID NO: 1 of the present invention), in cooperation with Es (212 bp; GenBank Accession No. J04617.1 (human elongation factor-1 alpha (EF-1α) promoter), nucleotides 397 to 608) and SV40 promoter (Sv) (269 bp; GenBank Accession No. MT086573.1, nucleotides 4403 to 4671).
The strength of promoters in dual-cassette vectors is unpredictable and relative positioning and strength of promoters affect expression interference. In order to practice the invention using the Specification and the state of the prior art as outlined above, the quantity of experimentation required to practice the invention as claimed would require the de novo determination of which a. a first transcription unit (TU) comprising a first promoter, a first nucleic acid sequence, and a first termination sequence; b. a second transcription unit (TU) downstream from said first TU; said second TU comprising a second promoter, a second nucleic acid sequence, and a second termination sequence; and c. a cytomegalovirus (CMV) core fragment (cC element) function as a duel-cassette vector to drive transgene expression in transduced cells. As supported by Applicant’s own disclosure and Boateng-Antwi et al., such analysis is replete with trial-and-error experimentation due to promoter interference between adjacent TUs. Also, see Curtin et al. Such experimentation represents an inventive and unpredictable undertaking in itself, with each of the many intervening steps, not providing any guarantee of success. Given the art recognized unpredictability of promoter activities in dual-cassette expression, this determination would not be routine and would require undue trial and error experimentation.
Due to the scope of the claims, one of skill in the art would be required to further undertake extensive trial and error experimentation to make and use the dual-cassette vector of the present claims. Since the specification fails to provide any real guidance for a dual-cassette vector other than one comprising the small-size 120 bp cC element (50 bp to +70 bp) (SEQ ID NO: 1 of the present invention), in cooperation with Es (212 bp; GenBank Accession No. J04617.1, nucleotides 397 to 608) and SV40 promoter (Sv) (269 bp; GenBank Accession No. MT086573.1, nucleotides 4403 to 4671), for modulating transcription interference between two TUs in dual-cassette LVs to drive transgene expression in transduced cells, and since promoter activities in dual-cassette expression is highly unpredictable, one of skill in the art would have been unable to practice the invention, without engaging in undue trial and error experimentation.
Thus, in view of the breadth of the claims, the lack of guidance, and the lack of working examples, the instant specification is not found to be enabling over the full scope claimed. Without further guidance, one of skill in the art would have to practice a substantial amount of trial-and-error experimentation, an amount considered undue and not routine, to practice the instantly claimed invention. Therefore, it is appropriate to reject the claims under 35 USC 112(a) for not being fully enabled.
The Wands factors have been weighed and favor undue experimentation.
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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 6 is indefinite because recitation of a GenBank accession number is not an appropriate means for identifying a sequence. See 37 CFR § 1.821(d) which states:
(d) Where the description or claims of a patent application discuss a sequence that is set forth in the “Sequence Listing” in accordance with paragraph (c) of this section, reference must be made to the sequence by use of the sequence identifier, preceded by “SEQ ID NO:” in the text of the description or claims, even if the sequence is also embedded in the text of the description or claims of the patent application.
Furthermore, in the event that there is an error or change to the sequence or annotation, the GenBank accession number is updated and thus will not remain constant over time. Therefore, different versions of any given sequence may appear in the GenBank Database at any given time. Since the record of a GenBank accession number is constantly updated, and an original accession number might become secondary to a newer accession number, the recitation of a GenBank accession number fails to distinctly claim the subject matter which applicant regards as the invention. Appropriate correction is required.
Conclusion
No claims are allowable at this time.
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to Terra C. Gibbs whose telephone number is 571-272-0758. The Examiner can normally be reached from 8 am - 5 pm M-F.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner's supervisor, Ram Shukla can be reached on 571-272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/TERRA C GIBBS/Primary Examiner, Art Unit 1635
