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 .
Election/Restrictions
Applicant’s election without traverse of Group I, corresponding to claims 1 – 10 in the reply filed on 05/11/2026 is acknowledged. Claims 1 and 11 have been amended. Claim 5 is cancelled.
Examiner also acknowledges applicant’s election of species:
Species I: Nucleic acid sequence encoding a HN50 construct – SEQ ID NO: 26
Species II: Amino acid sequence encoding a HN50 construct – SEQ ID NO: 27
Species III: pMYT1055 plasmid – SEQ ID NO: 29
Claims 11 – 21 are withdrawn from further consideration pursuant to 37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.
Claims 1 – 4 and 6 – 10 are under consideration.
Priority
This application also claims priority to US Provisional Application No. 63/344,252, filed on May 20, 2022.
Claim Rejections - 35 USC § 112 – Indefiniteness
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.
Claims 6 and 7 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.
Claim 6 is drawn to a nucleic acid sequence encoding an antigenic peptide comprising a sequence of at least 90% similarity to SEQ ID NOs: 5, 8, 11, 14, 17, 20, 23, 26, 44, 45, or combinations thereof. It is not clear whether the Applicants intend this limitation to read on 90% similarity of only a single SEQ ID NO, a combination of sequences that individually have 90% similarly to a single SEQ ID NO i.e. 90% similarity to SEQ ID NO: 5 and 90% similarity to SEQ ID NO: 26, or at least 90% similarity for a combination of SEQ ID NOs i.e. a 5% portion of SEQ ID NO: 5 and a 100% portion of SEQ ID NO: 26. It is unclear as to what gene the 90% similarity is related to. For purposes of compact prosecution and applying prior art, claim 6 was interpreted as 90% similarity of only a single SEQ ID NO.
Claim 7 is drawn to an amino acid sequence encoding an antigenic peptide comprising a sequence of at least 90% similarity to SEQ ID NOs: 3, 4, 6, 7, 9, 10, 12, 13, 15, 16, 18, 19, 21, 22, 24, 25, 27, 28, 30, 31, 32, or combinations thereof. It is not clear whether the Applicants intend this limitation to read on 90% similarity of only a single SEQ ID NO, a combination of sequences that individually have 90% similarly to a single SEQ ID NO i.e. 90% similarity to SEQ ID NO: 3 and 90% similarity to SEQ ID NO: 27, or at least 90% similarity for a combination of SEQ ID NOs i.e. a 5% portion of SEQ ID NO: 3 and a 100% portion of SEQ ID NO: 27. For purposes of compact prosecution and applying prior art, claim 7 was interpreted as 90% similarity of only a single SEQ ID NO.
Claim Rejections - 35 USC § 112 – Written Description
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 6 and 7 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.
The claims are broadly drawn to a genus comprising: a recombinant gene that has a nucleic acid sequence encoding an antigenic peptide comprising a sequence of at least 90% similarity to SEQ ID NOs: 5, 8, 11, 14, 17, 20, 23, 26, 44, 45, or combinations thereof and a recombinant gene that has an amino acid sequence encoding an antigenic peptide comprising a sequence of at least 90% similarity to SEQ ID NOs: 3, 4, 6, 7, 9, 10, 12, 13, 15, 16, 18, 19, 21, 22, 24, 25, 27, 28, 30, 31, 32, or combinations thereof. However, the Specification has failed to sufficiently describe the structural features that must be retained by members of the claimed genus as to establish a structure-function relationship with respect to protein function and regulation. There is not sufficient description of the structural features that must be retained to establish a functional relationship with respect to viral antigen regulation by proper trafficking of the antigen in and out of the cell.
The broadest reasonable interpretation of the claims encompasses innumerable permeations of nucleic acids and innumerable permeations of proteins. The Specification fails to disclose which regions of a sequence must be retained with respect to function. With respect to the elected species SEQ ID NOs 26 and 27, the Specification fails to disclose which regions of SEQ ID NOs: 26 or 27 can be mutated, deleted, truncated, etc., or which regions of SEQ ID NOs: 26 or 27 must be retained with respect to function. The claims improperly define the genus based on what it does, in this case, viral antigen trafficking and regulation, —not what it is. When narrowed down to even a singular sequence, the claims encompass an innumerable number of permeations. For example, SEQ ID NO: 26 encodes a secretion signal fused to a NDV HN protein. SEQ ID NO: 26 is 1410 nucleic acids in length. A variant sharing 90% identity to SEQ ID NO: 26 can have anywhere from 1 to 141 substitutions, deletions or additions in any combination along any length of the sequence. Thus, just for substitutions with canonical nucleic acids alone, the instant claims encompass an enormous genus (4141 = 7.8 x 1084) comprising trillions upon trillions of sequences.
SEQ ID NO: 27 is the amino acid sequence that is translated from SEQ ID NO: 26. SEQ ID NO: 27 is 469 amino acids in length. A variant sharing 90% identity to SEQ ID NO: 27 can have anywhere from 1 to 46 substitutions, deletions or additions in any combination along any length of the sequence. Thus, just for substitutions with canonical amino acids alone, the instant claims encompass an enormous genus (2057 = 4.95 x 1027) comprising trillions upon trillions of sequences.
While the claims are drawn to a nebulous genus of ill-defined variants, the Specification and Drawings have only adequately described and successfully reduced to practice 4 variants of NDV HN protein (¶0262).
At best, the Specification contemplates the use of BLAST to identify functional homologs based on sequence homology (¶0175). However, this is not sufficient to describe members of the claimed genus because such methods access online databases that are continually being updated as sequencing technology improves. As a result, they are not a static source of information. Thus, one of skill in the art would readily appreciate that relying on a non-patent source that is continuously subject to change as a means to identify members of the claimed genus does not sufficiently meet the written description requirement.
Moreover, Friedberg (Brief Bioinformatics, 7:225-242 (2006)) teaches that homology-based transfer is not reliable for functional annotation even with high alignment percentages (page 227, second column). Friedberg also teaches that identification of functionally significant sub-regions is critical to functional annotation, and that often addition, deletion, or re-shuffling
of domains can lead to errors in annotation (page 227, second column; page 228, first paragraph). Furthermore, Friedberg teaches that sequence-based tools are just not sensitive enough to identify functional protein similarity as databases get larger, and diversity of sequences gets larger (page 228, first full paragraph).
Thorton et al. (Nature Struct. Biol, Struct. Genom. Suppl. Nov., 991-994 (2000), hereinafter “Thorton”) teaches that the same protein structure is often seen in apparently different homologous families with different functions. Thorton further describes examples of little correlation between specific enzyme function and overall protein structure (page 992, right column, at lines 2-10). Thus, when taken with the teachings of Friedberg and Thorton, one of skill in the art would readily appreciate that sequence homology alone cannot serve as the basis to describe members of the genus that have the recited function.
In the absence of a representative number of examples, the Specification must at least
describe the structural features that are required for the claimed function, in this case, with regards to SEQ ID NO: 26 or 27 viral antigen function and regulation.
However, as discussed above, the Specification fails to describe any substantive structural limitations as to establish a structure-function relationship with respect to function, let alone the various improved properties required throughout the instant claims. Applicant merely offers a cursory statement that any nucleic acid sequence with 90% identity to SEQ ID NOs: 26 or 27 will work.
Accordingly, the claims as currently written are not adequately described and one of skill in the art would readily appreciate that Applicant was not in possession of the claimed genus before the effective filing date of the claimed invention.
Claim Rejections - 35 USC § 102
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.
Claim(s) 1 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Khulape et al (Acta virologica, 2015, 10.4149/av_2015_03_240, hereinafter, “Khulape”).
Khulape discloses the development of recombinant antigen-based immune assays and subunit vaccines for Newcastle disease virus (NDV) (Abstract). Khulape discloses that the outer membrane glycoprotein, hemagglutinin-neuraminidase (HN) can be expressed in a fungal cell (Abstract). Khulape discloses that fungal cells offer eukarytoic environment for processing and posttranslational modifications like glycosylation, as well as higher growth rate and accessible genetic manipulation (Abstract).
Regarding claim 1, Khulape discloses the production of HN under a GAL10 promoter in Saccharomyces cerevisiae (Abstract).
Accordingly, Khulape anticipates the claimed invention.
Claim Rejections - 35 USC § 103
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.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Khulape as applied to claim 1 above, and further in view of Emalfarb et al (US20200215183A1, hereinafter, “Emalfarb”).
As discussed above, claim 1 was anticipated by Khulape. Khulape discloses the production of NDV HN in fungal cells (Abstract).
The reference does not disclose a Thermothelomyces heterothallica fungal cell to produce NDV HN proteins.
However, Emalfarb teaches using a Myceliophthora thermophila strain C1 fungus to express recombinant influenza surface proteins (Abstract). Emalfarb teaches the producing influenza hemagglutinin (HA) and neuraminidase (NA) proteins (Claim 26, 34). Emalfarb also teaches the design of plasmids to enhance protein secretion by including C1 regulatory elements (Figure 2C, ¶0011, 0017). Emalfarb teaches that using a fungal cells over chicken eggs results in reduced time and expense (¶0005).
Regarding claim 2, Emalfarb teaches the use of Myceliophthora thermophila strain C1 to produce viral proteins (Abstract). As evidenced by the instant application that Thermothelomyces heterothallica was previously known as Myceliophthora thermophila (Instant application ¶0186).
Khulape and Emalfarb are considered to be analogous to the claim invention because they aim to produce viral proteins using fungal cells. Khulape discloses the production of NDV HN in fungal cells (Abstract). Emalfarb teaches using a Thermothelomyces heterothallica C1 fungus to express recombinant HA and NA influenza surface proteins (Abstract, claims 26, 34).
Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to produce NDV HN, as taught by Khulape, in a Thermothelomyces heterothallica C1 strain, as taught by Emalfarb, because doing so would increase protein production while reducing production time and cost. One of ordinary skill in the art would have had a reasonable expectation of success producing NDV HN in Thermothelomyces heterothallica C1 given that producing NDV HN in fungal cells and producing viral proteins in Thermothelomyces heterothallica C1 was well known, has been successfully demonstrated, and commonly used in the prior art.
Claims 3 and 4 are rejected under 35 U.S.C. 103 over Khulape and Emalfarb as applied to claim 2 above, and further view of Dyadic et al (Continued Success, Great Potential To Use C1 As Production Platform For rVaccines In Human & Animals, 2020, hereinafter, “Dyadic”).
As discussed above, claim 2 was rendered prima facie obvious by Khulape and Emalfarb.
As discussed above, Khulape discloses the production of NDV HN in fungal cells. Emalfarb teaches using a Thermothelomyces heterothallica C1 fungus to express recombinant HA and NA influenza surface proteins.
The references do not teach using a DNL155, DNL157, DNL159, M5355, or M5739 a Thermothelomyces heterothallica C1 or a engineered a Thermothelomyces heterothallica C1 producing Man3, G0, or G2 glycans.
However, Dyadic teaches the development of C1 strains for the production of rVaccines (Slide 1). Dyadic teaches the production of viral antigens that are not produced in a baclovirus system (Slide 7). Dyadic teaches the production of Rift Valley Fever Virus (RVFV) antigens, among other antigens from other viruses, produced in an engineered DNL155 C1 strain (Slide 7). Furthermore, Dyadic teaches that this engineered fungal strain increases viral antigen production in decreased time (Slide 3).
Regarding claim 3, Dyadic teaches producing viral antigens in a DNL155 C1 strain (Slide 7).
Regarding claim 4, Dyadic teaches a glycoengineered C1 producing Man3 (Slide 9).
Khulape, Emalfarb, and Dyadic are considered to be analogous to the claim invention because they aim to produce viral proteins using fungal cells. Khulape discloses the production of NDV HN in fungal cells (Abstract). Emalfarb teaches using a Thermothelomyces heterothallica C1 fungus to express recombinant HA and NA influenza surface proteins (Abstract, claims 26, 34). Dyadic teaches producing viral antigens in DNL155 C1 and Man3 producing C1 strains (Slide 7, 9).
Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to produce NDV HN, as taught by Khulape, in a DNL155 derived Thermothelomyces heterothallica C1 strain or Man3 producing C1 strain, as taught by Emalfarb and Dyadic, because doing so would increase protein production while reducing production time and cost. One of ordinary skill in the art would have had a reasonable expectation of success producing NDV C1 in a DNL155 derived Thermothelomyces heterothallica C1 strain or Man3 producing C1 strain given that producing NDV HN in fungal cells and producing viral proteins in a DNL155 derived Thermothelomyces heterothallica C1 strain or Man3 producing C1 strain was well known, has been successfully demonstrated, and commonly used in the prior art.
Claims 6, 7, and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Khulape as applied to claim 1 above, and further in view of Emalfarb and Wiseman et al (Infection, Genetics, and Evolution, 2018, 10.1016/j.meegid.2018.09.017, hereinafter, “Wiseman”).
As discussed above, claim 1 was anticipated by Khulape. Khulape discloses the production of NDV HN in fungal cells (Abstract).
The reference does not disclose SEQ ID NO: 1, 26, and 27.
The instant application discloses that SEQ ID NO: 26 is the nucleic acid coding sequence for a secretion signal and synthetic NDV HN protein (¶0003). The instant application discloses that the translation of this sequence gives the amino acid sequence of SEQ ID NO: 27 (¶0003).
Emalfarb teaches the first 51 nucleic acids which is a secretion signal. Emalfarb also teaches that this signal is fused to the N terminus of the viral antigen to be produced.
Wiseman teaches the genetic analysis of Avian avulvirus-1, also known as Newcastle Disease Virus (Introduction ¶1). Wiseman teaches the discovery of three sub-genotypes of NDV (Highlights). Wiseman also teaches the creation of a phylogenic tree based on the newly discovered NDV strains (Figure 2).
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Regarding claims 6 and 7, Emalfarb teaches a secretion signal defined by a nucleic acid sequence that is 100% identical to the first 51 nucleic acids of SEQ ID NO: 26 (corresponding to amino acids 1 – 465 of SEQ ID NO: 27, reproduced below). SEQ ID NO: 27 is the amino acid translation of SEQ ID NO: 26 (Instant application ¶003). Wiseman teaches an NDV HN amino acid sequence that has 98% sequence similarity to amino acids 18 – 465 of SEQ ID NO: 27 (corresponding to nucleic acids 52 – 1410 of SEQ ID NO: 26) (reproduced below, Query is SEQ ID NO: 27, Sbjct is Wiseman). While Wiseman does not explicitly teach the nucleic acid sequences of SEQ ID NO: 26, the amino acid taught by Wiseman would translate to the nucleic acid sequence of SEQ ID NO: 26. Thus, the claimed nucleic acids from 52 – 1410 of SEQ ID NO: 26 is reasonably encompassed by Wiseman. Emalfarb also teaches the fusion of the secretion signal with viral antigens (¶0039, Figure 2C).
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Regarding claim 9, Emalfarb teaches the nucleic acid sequence of the secretion signal but does not explicitly teach the amino acid sequences of SEQ ID NO: 1. However, translating the amino acid sequences of instant SEQ ID NO: 1 result in the amino acid sequence taught by Emalfarb (reproduced below). Thus, the claimed sequence is reasonably encompassed by Emalfarb.
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Khulape, Emalfarb, and Wiseman are considered to be analogous to the claim invention because they deal with viruses. Khulape discloses the production of NDV HN in fungal cells (Abstract). Emalfarb teaches using a Thermothelomyces heterothallica C1 fungus to express recombinant HA and NA influenza surface proteins as well as using a secretion signal fused to the viral antigens (Abstract, claims 26, 34). Wiseman teaches the amino acid sequence of teaches a 98% sequence similarity of the HN protein encoded by nucleic acids 52 – 465 of SEQ ID NO: 27 (reproduced above).
Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to produce a secretion signal fused to a NDV HN protein in a Thermothelomyces heterothallica C1 strain because doing so would traffic the proteins successfully throughout the cells. One of ordinary skill in the art would have had a reasonable expectation of success produce a secretion signal fused to a NDV HN protein in a Thermothelomyces heterothallica C1 strain given fusing a secretion signal to a viral antigen to increase production of the viral antigen is well known, has been successfully demonstrated, and commonly used in the prior art.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Khulape as applied to claim 1 above, and further in view of Emalfarb 2 et al (WO2020161682A1, hereinafter, “Emalfarb 2”).
As discussed above, claim 1 was anticipated by Khulape. Khulape discloses the production of NDV HN in fungal cells (Abstract).
The reference does not disclose a bgl8 promoter to drive NDV HN expression.
However, Emalfarb 2 teaches using a Thermothelomyces heterothallica C1 strain to express exogenous cannabinoid proteins (Abstract). Emalfarb 2 teaches the C1 strain has been genetically modified to better produce exogenous proteins (Page 4 Lines 2 – 6). Emalfarb 2 also teaches the design of plasmids to enhance protein secretion by including C1 regulatory elements (Page 47 Lines 2 – 5, Table 3).
Regarding claim 10, Emalfarb 2 teaches a bgl8 promoter can be used to drive exogenous protein production (Page 47 Lines 2 – 5, Table 3).
Khulape and Emalfarb 2 are considered to be analogous to the claim invention because they aim to produce viral proteins using fungal cells. Khulape discloses the production of NDV HN in fungal cells (Abstract). Emalfarb 2 teaches a bgl8 promoter can be used to drive exogenous protein production (Page 47 Lines 2 – 5, Table 3).
Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to drive expression of NDV HN, as taught by Khulape, using a bgl8 promoter in a Thermothelomyces heterothallica C1 strain, as taught by Emalfarb 2, because doing so would increase protein production while reducing production time and cost. One of ordinary skill in the art would have had a reasonable expectation of success driving NDV HN with a bgl8 promoter in Thermothelomyces heterothallica C1 given that producing NDV HN in fungal cells and producing viral proteins using a bgl8 promoter in Thermothelomyces heterothallica C1 is well known, has been successfully demonstrated, and commonly used in the prior art.
Allowable Subject Matter
Claim 8 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. Claim 8 depends on claim 1 which, as discussed, is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Khulape. However, the exact sequence of SEQ ID NO: 29 encoding an episomal vector is not found in the prior art. Therefore, if rewritten claim 8 would be allowable if it is independent of claim 1.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Danyal H Alam whose telephone number is (571)272-1102. The examiner can normally be reached M - F 9am - 5pm.
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/DANYAL HASSAN ALAM/ Examiner, Art Unit 1672
/THOMAS J. VISONE/ Supervisory Patent Examiner, Art Unit 1672
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