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 of the invention of Group 1 (claim 1-7 drawn to methods of detecting AHPND or AHPND susceptible organisms) in the reply filed on 06/30/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Applicants additional elections of the particular species of: (i) the combination of four genes that is CRTS-P; PPAE2, CHYA and SP; and (ii) the particular organism that is shrimp, are also acknowledged.
Claims 9-11, 13-17 and 19-23 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06/30/2025.
Specification
The disclosure is objected to because of the following informalities:
The specification as several recitations of “CRSTP (SEQ ID NO: 34)” (see for example paras [0274] and [0274]), but the recitation of “CRSTP” is not a disclosure of an amino acid sequence, it appears to be the gene symbol for the crustin P gene. Additionally, the gene symbol is not consistent in the specification, where it appears as: CRST-P; CRSTP; and CRST P.
The specification has several instances where the gene symbol “PPAE2” is incorrectly written as “PPEA2”.
Appropriate correction is required.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 - 1.825.
The sequence disclosures are located in Figures 6A and 6B of the drawings. These sequences are not in the sequence listing, and there are no sequence idnetifiers (SEQ ID NO:) in either the drawings or in the description of the drawings atr para [0036] on page 10 of the specification.
Required response – Applicant must provide:
A "Sequence Listing" part of the disclosure, as described above in item 1); as well as
An amendment specifically directing entry of the "Sequence Listing" part of the disclosure into the application in accordance with 1.825(b)(2);
A statement that the "Sequence Listing" includes no new matter in accordance with 1.825(b)(5); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter;
If the "Sequence Listing" part of the disclosure is submitted according to item 1) b), c), or d) above, Applicant must also provide:
A replacement CRF in accordance with 1.825(b)(6); and
Statement according to item 2) a) or b) above.
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Objections
Claim 1 is objected to because of the following informalities:
The claims recite a plurality of gene symbols, where at the first instance of the recitation a symbol the symbol should be accompanied by the full gene name. For example, in line 5 of claim 1: (a) one or more genes selected from the group consisting of: SEP8 (Serpin8), BGBP (β-glucan binding protein), CRST-P (Crustin P) …
The gene symbol for Custin P in not consistent, where it is presented without a hyphen on lines 5-6 of claim 1 (i.e.: “CRTS-P” versus “CRST P”).
The gene symbol for Chymotrypsin A is not capitalized in line 13 of claim 1 (i.e.: “ChyA” versus “CHYA”).
The claims has several instances where the gene symbol “PPAE2” is incorrectly written as “PPEA2”.
Appropriate correction is required.
Claim Rejection - Improper Markush Grouping
Claims 1-7 are rejected under the judicially approved "improper Markush grouping" doctrine. (See Federal Register, Vol. 76, No. 27, Wednesday, February 9, 2011, page 7166). This rejection is appropriate when the claim contains an improper grouping of alternatively useable species. See In re Harnisch, 631 F.2d 716, 719-20 (CCPA 1980). A Markush claim contains an "improper Markush grouping" if: (1) the species do not share a common use; or (2) the species of the Markush group do not share a "single structural similarity" wherein the structural similarity is essential to a common use. See MPEP § 803.02 and MPEP § 2117.
Here each species is considered to be a different method requiring the analysis and detection of any combination or subcombination of the recited genes.
The recited alternative elements do not share a single structural similarity, as each method relies on the detection of a different polynucleotide sequence (an mRNA resulting from transcription of a different gene). Each transcript and gene locus has a different chemical structure in that it consists of a different polynucleotide sequence context. And each gene/transctipt has a different biological activity in that it has a different specificity of hybridization required for analysis/detection, and may encode a distinct protein having a different biological activity. Thus, the species do not share a single structural similarity or biological activity. The only structural similarity present is that all of the genes and transcripts may be present as nucleic acids. The fact that the biomarker genes comprise nucleotides per se does not support a conclusion that they have a common single structural similarity because the structure comprising a nucleic acid alone is not essential to the common activity of being correlated with AHPND susceptibility or resistance, as asserted by the specification. Accordingly, while the different genes are asserted to have the property of expression associated with AHPND, they do not share a single structural similarity essential to this activity.
Here it is clear that the asserted common use does not flow from any broadly ascribed common structure (see MPEP 2117(II)(B)). The common use of being a related to AHPND is particular to each different genes because of some particular biological function/role of each particular gene product (i.e.: the encoded protein), not based on some particular common structural feature shared among the different genes themselves.
Note that when the Markush grouping is for alternatives of chemical compounds, the alternatives are regarded as being of a similar nature where the following criteria are fulfilled:
(A) all alternatives have a common property or activity; AND
(B)(1) a common structure is present, that is, a significant structural element is shared by all of the alternatives; OR
(B)(2) in cases where the common structure cannot be the unifying criteria, all alternatives belong to a recognized class of chemical compounds in the art to which the invention pertains.
The phrase “significant structural element is shared by all of the alternatives” refers to cases where the compounds share a common chemical structure which occupies a large portion of their structures, or in case the compounds have in common only a small portion of their structures, the commonly shared structure constitutes a structurally distinctive portion in view of existing prior art, and the common structure is essential to the common property or activity.
The phrase “recognized class of chemical compounds” means that there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention, i.e. each member could be substituted one for the other, with the expectation that the same intended result would be achieved.
In the present situation, there is no evidence of record to establish that it is clear from their very nature that the different genes are associated with AHPND. Nor is there an expectation that all of the different genes will behave the same way, where the specification teaches that in fact different genes show different expression levels associated AHPND in different populations studied in different bioassays (e.g.: Figures 3 and 4).
Following this analysis, the claims are rejected as containing an improper Markush grouping.
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 1-7 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.
Claims 1-7 are unclear over recitation of the limitation “the sample contains”, as recited in line 24 of claim 1. The is no antecedent basis for any “sample” in the claim, and so it is unclear what is required or intended by recitation of the phrase “the sample”.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-7 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (abstract idea; natural phenomenon) without significantly more.
The claim(s) recite(s) “detection of the AHPND signature indicates that the organism or cell(s) thereof is tolerant to AHPND or that the sample contains at least one cell that is tolerant to AHPND or detection of the AHPND signature indicates that the organism or cell(s) thereof is susceptible to AHPND or that the sample contains at least one cell that is susceptible to AHPND” (as recited in claim 1; with similar limitations recited in claim 7). This limitation is directed to the association between gene expression and susceptibility to a pathology; where such an association is the result of biological processes within the organism the claims are directed to a natural phenomenon (see MPEP 2106.04(b)(I)). Furthermore, where the limitation sets forth that “the AHPND signature indicates” a phenotype, the claims are directed to a mental process that is the evaluation of data and information to reach a conclusion of judgement, which is an abstract idea (MPEP 2106.04(a)). Such an abstract idea is also recited in claim 6 which requires the comparison of data to a control to determine increased or decreased expression.
This judicial exception is not integrated into a practical application because the claims end with the evaluation of data to reach a conclusion, which is not a practical step, but is an abstract idea, as noted above. The claims do not require any additional practical/tangible steps that are performed as a result of the evaluation of expression signatures to detect AHPND or susceptibility to AHPND.
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims require only the detection of gene signatures (i.e.: a measurement of gene expression levels). This step, which is the required pre-solution data gathering activity (MPEP 2106.05(g)) required to perform the judicial exception(s) to which the claims is/are directed, is recited at the highest level of generality. Additionally it is noted that the collection of gene expression data related to Vibrio infection in shrimp and prawns was well understood, routine and conventional in the prior art. Vogeley et al (2019) (cited on the PTO-892 of 05/02/2025) teaches analysis of gene expression in shrimp, and Rao et al (2015) teaches analysis of gene expression in prawns using RNA-seq, which provides a measure of expression of every transcript in the sample.
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 1-7 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 (as consonant with Applicants’ election):
A method of determining that an organism is susceptible or tolerant to acute hepatopancreatic necrosis disease (AHPND), the method comprising:
obtaining a sample of hepatopancreas tissue from a test organism, where organism is a shrimp that has been exposed to an etiological agent of AHPND;
detecting in the sample the level of mRNA expression of each gene of the group consisting of: SP(serine protease); CRST-P (crustin-P); PPAE2 (prophenol oxidase activation system 2); and CHYA (chymotrypsin A); and
comparing the levels of mRNAs detected in the sample from the test organism to reference levels of SP, CRST-P, PPAE2, and CHYA mRNAs in a sample of hepatopancreas tissue from a control shrimp that has been exposed to an etiological agent of AHPND; wherein
the control shrimp is AHPND susceptible, the level of SP in the sample from the test organism is decreased compared to the reference level of SP, the level of each of CHYA, PPAA2 and CRST-P is increased compared to the reference level of each of CHYA, PPAE2 and CRST-P, and the test organism is determined to be susceptible to AHPND; or
the control shrimp is AHPND tolerant, the level of SP in the sample from the test organism is increased compared to the reference level of SP, the level of each of CHYA, PPAE2 and CRST-P is decreased compared to the reference level of each of CHYA, PPAE2 and CRST-P, and the test organism is determined to be AHPND tolerant.
does not reasonably provide enablement for the methods as claimed which encompass the detection of any levels and any comparison with any references, as wells as the detection of expression in any sample type from any organism and the use of any analyte to determine that an organism is susceptible or tolerant to AHPND. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Nature of the invention and the breadth of the claims
The methods of the claims are directed to the detection of AHPND or AHPND susceptibility in an organism comprising the detection of a gene signature comprising (as consonant with the Election) SP, CHYA, PPAE2 and CRST-P. The claims encompass the analysis of any sample type (e.g.: hepatopancreas, hemocytes, muscle, ovaries, testes) for any subject organism, the detection of any levels (e.g.: any absolute levels, or relative level compared to an internal control such as a housekeeping gene, or levels compared to any reference level) and the use any analyte (e.g.: mRNA or protein) to determine a signature.
Direction provided by the specification and working example
The instant specification provides examples (p.81-94) of analysis of gene expression in shrimp challenged with Vibrio parahaemolyticus bacteria, and comparisons (e.g.: para [0264]) of gene expression levels among known populations that are AHPND susceptible (i.e.: P1 populations) and AHPND tolerant (i.e.: P2 populations). The specification does not provide any analysis gene expression in non-shrimp organisms.
The specification teaches the particular detection of increased levels of expression of CHYA, CRST-P and PPAE2, and decreased levels of SP, in hepatopancreas tissue of AHPND susceptible shrimp as compared to AHPND tolerant shrimp.
The specification provides for the analysis of gene expression in hepatopancreas tissue (e.g.: para [0274]) by measuring mRNA expression levels (e.g.: para [0264]). The specification does not teach any analysis of other tissues or other gene expression analytes.
State of the art, level of skill in the art, and level of unpredictability
While the state of the art and level of skill in the art with regard to the analysis of gene expression levels in any sample is high, the unpredictability in associating any expression levels with a particular pathological risk, such as AHPND, is higher. Such unpredictability is demonstrated by the related art and the instant specification.
Because the claimed methods encompass the examination of samples from any organism, while the specification provides only an example of shrimp gene expression analysis, it is relevant to point out that Hoshikawa et al (2003) teaches unpredictability with regard to applying gene expression results among different organisms. The reference teaches the analysis of gene expression in lung tissue in response to hypoxic conditions which lead to pulmonary hypertension (Fig. 1). The reference teaches that the gene expression profile in mouse is different from that observed in rat (Tables 1-4; p.209 - Abstract). Thus, it is unpredictable as to whether or any genes that are AHPND-related in, shrimp are similarly associated in any other different non-shrimp organism.
Similarly, because the claims encompass examining samples from any source (e.g. any tissue or body fluid type), it is relevant to point out the unpredictability with regard to the analysis of gene expression profiles obtained from different sample types. Cobb et al (2002) teaches the analysis of gene expression in spleen and liver sample from septic mice. Notably, the reference teaches that, when compared to a non-septic sample, the relevant expression profiles of the septic mouse spleen and the septic mouse liver contain different nucleic acids at different levels (Table 1; p.2714, middle col., lns.2-8). It is thus unpredictable as to how one might extrapolate gene expression levels from hepatopancreas tissue (as provided in the instant specification) to the analysis of gene expression in a sample obtained from any other source (e.g. any different tissue or fluid). The difference in gene expression levels among different sample types is further suggested by the teachings of the instant specification (e.g.: para [0274]).
Because the claims encompass detecting any level of gene expression, and any comparisons of gene expression levels, it is relevant to point out that Cheung et al (2003) teaches that there is natural variation in gene expression among different individuals. The reference teaches an assessment of natural variation of gene expression in lymphoblastoid cells in humans, and analyzes the variation of expression data among individuals and within individuals (replicates) (p.422, last paragraph; Fig 1). The data indicates that, for example, expression of ACTG2 in 35 individuals varied by a factor of 17; and that in expression of the 40 genes with the highest variance ratios, the highest and lowest values differed by a factor of 2.4 or greater (Fig 3). It is thus unpredictable as to whether or not any combination of gene expression levels (i.e.: combined to form a score using any method) would effectively characterize sepsis severity or response to treatment. Similar, the requirement for particular comparisons (i.e.: to expression levels in susceptible or tolerant shrimp exposed to an AHPND agent) is further demonstrated by the teachings of the specification. For example, when considering the data of Figures 3A, 3B and 3C, there are some examples where there the same general change in gene expression in P1 versus unchallenged organisms and P2 versus unchallenged organisms (e.g.: in both P1 and P2, CHYA expression is increased as compared to unchallenged).
Quantity of experimentation required
A large and prohibitive amount of experimentation would have to be performed in order to make and use the claimed invention in the full scope as claims. One would have to establish that any particular determined level of gene expression of a gene consonant with the Election is indicative of AHPND susceptibility. Within the scope of the claims, this would require large case:control studies for the analysis of samples in different organisms, and examining samples from different sources (e.g. blood, tissues), in an attempt to establish that any level of gene expression (e.g. any amount of up or down regulation) is reliably associated with AHPND. Even if such a large amount of experimentation were to be performed, there is no assurance that one would in fact identify any gene expression other than those particular taught by the application as associated with AHPND.
Conclusion
Taking into consideration the factors outlined above, including the nature of the invention and breadth of the claims, the state of the art, the level of skill in the art and its high level of unpredictability, the provided guidance and the description of the working example, it is the conclusion that an undue amount of experimentation would be required to make and use the invention as claimed.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEPHEN THOMAS KAPUSHOC whose telephone number is (571)272-3312. The examiner can normally be reached M-F, 8am-5pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Anne Gussow can be reached at (571)272-6047. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Stephen Kapushoc
Primary Examiner
Art Unit 1684
/STEPHEN T KAPUSHOC/Primary Examiner, Art Unit 1683