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 with traverse of species tkt-hrcA, Bifidobacteirum, and the oligonucleotides ACAAGCCGG, SEQ ID NO: 23-26 and 65-66 listed in claim 2 in the reply filed on 7/10/2025 is acknowledged. The traversal is on the ground(s) that subsets of the recited oligos could also be used. This is not found persuasive because (1) there is no claim that is clearly inclusive of subsets, and applicant was advised if such a claim was intended that intent should be clarified with claim language and (2) the search of each different oligo individually and in subsets would pose a serious burden on the examiner as nine different oligos could be taken in many subset groups.
The requirement is still deemed proper and is therefore made FINAL.
Claim 9 is withdrawn from prosecution because the two genetic elements elected do not appear to meet both criteria required by the claim. While HrcA is clearly in “the HrcA family” it is not a lysR-type transcriptional regulator.
Claim Objections
Claims 5 and 6 and 8 are objected to because of the following informalities:
Claims 5 and 8 do not end in a period.
In claim 5, “Weisella” is a typographical error and should be “Weissella”.
Claim 6 missing a comma between Pedicoccus and Streptococcus and also a comma is missing between Bacillus and Streptomyces.
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 – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
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.
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 Figures 2, 10, 13.
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.
Priority
Applicant states that this application is a continuation or divisional application of the prior-filed application. A continuation or divisional application cannot include new matter. Applicant is required to delete the benefit claim or change the relationship (continuation or divisional application) to continuation-in-part because this application contains the following matter not disclosed in the prior-filed application:
The instant claims set forth a method to “identify and quantify a target microorganism” “with” an HPME that comprises two open reading frames separated by a promoter region. The claim sets forth that the recited HPME is less than 2000 base pairs in length and has detectable means attached thereto. The options for the detectable means are recited in the claim.
The specification provides discussion of a “reporter molecule,” and those specifically listed in the claims at page 24, lines 13-18. In this context, the specification teaches that the possible applications of the HPME target sequences include “oligonucleotides or xeno-nucleic acid aptamers such as locked nucleic acid oligos to be used as a probe marked with a reporter molecule (e.g. Fluorescein, FAM, HEX, NED, TAMRA, R6G, JOE, VIC, Cyanine dyes, AlexaFlour dyes, quantum dots) for fluorescence molecular applications mediated by hybridization….” The specification does not define “oligonucleotide” or “oligo,” so these terms must be given their customary meaning which implies a molecule of “short” length having relative few nucleotide bases. (See enclosed definition, “oligonucleotide”). The specification additionally discusses FAM labelled primers (see figure 3 description, for example) and the TaqMan method that employs a probe with a “fluorescent reporter” at one end and a quencher at the opposite end.
The claimed HPME structures which include two ORF and a promoter region would be around 2000 base pairs in length (or longer), and not reasonably considered an “oligonucleotide” or a “primer” or a TaqMan probe within the customary meaning of these phrases. The specification does not describe or contemplate molecules of this length attached to a reporter molecule. Therefore, the newly added amendment is not disclosed in the parent application.
The claim language is not rejected under new matter because it is present in the claims filed on the actual filing date of this current application.
The effective filing date of the instant claims is that date: 7/23/2023.
Improper Markush Grouping
Claims 1-8 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of the mleA-mleR marker, the tkt-hrcA marker, and the hrcA-GrpE marker is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: each marker is structurally distinct encompassing nucleotide sequences not expected to have any common identity, and are set forth as having different utilities within the claim which states the markers are for identification of Lactobacillales order, Bifidobacterium family, and Bacillus family, respectively.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
If applicant amends the claim to overcome the Improper Markush Rejection, applicant is advised to also review claims 3, 5, and 6 to ensure that the species listed appropriate.
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, 3-9 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. The claim(s) does/do not fall within at least one of the four categories of patent eligible subject matter because although the preamble of the claim sets forth that it is a “method” the claims do not recite any steps.
Claim Rejections - 35 USC § 112
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 1-8 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 1 is indefinite when it recites that the claimed marker is a “microbial genome sequence” because a “sequence” is information but the rest of the claim appears to be referring toward a nucleic acid molecule. It’s unclear how a “sequence” can have a detectable means attached to it. Amending the claim to clearly set forth that the HPME comprises a nucleic acid molecule will overcome this rejection.
Claim 1 is also indefinite when it recites “having detectable means attached thereto” since the “means” is plural. It is not clear if this intends to require different distinct means selected from the list attached to a single marker, or if the claim is meant to require only that “a” detectable means is attached to the HPME.
Claim 1 contains the trademark/trade name “AlexaFlour®”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a detectable means and, accordingly, the identification/description is indefinite.
Claim 1 is further indefinite because it sets forth in the preamble of the claim the intended purpose of a method but the claim does not any active, positive steps delimiting how this “application” is actually practiced. See MPEP 2173.05(q).
With regard to claim 1, the claim recites “identification and quantification of the Bifidobacterium family” and this makes the metes and bounds of the claim unclear since “Bifidobacteirum” is a genus, not a family. It is unclear what microorganisms are meant to be included in this recitation.
With regard to the elected species, claim 1 recites “the gene tkt coding for the Transkelotase enzyme” and “the gene hrcA coding for the HrcA transcriptional regulator” but it is unclear which genes are “the” genes referred to in the claim since there is no antecedent basis for this language and there are many different tkt and hrcA genes from many different organisms.
Claim 2 taken in its entirety is unclear because claim 1 requires that the HPME that comprises two open reading frames separated by a noncoding nucleotide sequence is labled, and it is unclear how the method is intended to be carried out with this labeled molecule and the target markers consisting of the sequences recited in claim 2. It is unclear how all of the sequences interact to result in a functional method and there are clear method steps describing how the molecules interact in the claim.
In claim 6, the phrase “and Bacillus Streptomyces, Saccharomyces” is indefinite because it is unclear how these three elements are related to one another and to the rest of the claim since the claim language lacks a conjunction between the three elements.
In claim 7, the phrase “said extragenic region” lacks proper antecedent basis because claim 1 neither recites nor requires an “extragenic region”. Claim 1 does recite “a noncoding nucleotide sequence…being a promoter region” and it is not clear if claim 7 is meant to be referring to this promoter region. If so, it is unclear how claim 7 is meant to further limit the promoter region since promoter regions are already non coding regions.
Claims 4, 5, 6, and 8 refer to “said microbial genome nucleotide sequence” or “the microbial genome nucleotide” and these phrases lack proper antecedent basis in claim 1. Claim 1 does recite “a microbial genome sequence” and it is not clear if these phrases are referring to this sequence or to some portion of this sequence or something else.
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 1-8 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 instant claims set forth a method to “identify and quantify a target microorganism” “with” an HPME that comprises two open reading frames separated by a promoter region. The claim sets forth that the recited HPME is less than 2000 base pairs in length and has detectable means attached thereto. The options for the detectable means are recited in the claim.
The claims set forth that the HPME marker comprises “two genetic elements” “each and Open Reading Frame coding for a protein” with an HPME wherein the two genetic elements are the tkt gene and the gene hrcA.
Furthermore, the specification does not provide the structure of a single “microbial genome sequence” that comprises the required structures and that has a length less than or equal to 2000 base pairs.
The specification teaches that a “need and importance … for the identification of specific target sequences which are useful for identification and quantification of microorganisms and viruses for biomedical and biotechnological purposes (p. 5).”
The specification at page 6 states clearly that a HPME must comprise at least one ORF, complete or partial, and the claim sets forth that the HPME comprises “at least one primary protein encoding gene.”
The specification teaches that a partial ORF in an HPME is “conserved in more than one species” and also is divergent in other species. The specification explains that the “target marker” will be advantageous because it has SNP or insertions/deletions, but is present in different species of different genus. It is often characterized by two level of specificity, polymorphic regarding nucleotide content and length (p. 7).
With regard to the elected invention, that is a marker for identification and quantification of microorganisms within the “Bifidobacterium family”, the specification teaches
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This suggests that the scope of the disclosed marker can be as few as nine nucleotides. This marker does not appear to be within the scope of the claims because a nonamer does not comprise two open reading frames separated by a promoter. Likewise, the disclosure in Figure 10 teaches exemplary HPME tkt-hrcA markers, none of which appear to be within the scope of claim 1 since these have “partial sequence” from two genes (specification p. 14, l. 23-24) and do not comprise two open reading frames separated by a promoter, as required by each claim. Even if they were within the scope of claim 1, these sequences do not provide any way to predict the structure of additional versions of the tkt-hrcA marker other than those that are disclosed in the figure. Common structural attributes are not described. The general knowledge in the art of polymorphic makers does not provide an indication of how the structure of the disclose markers is representative of unknown marker sequences that are not disclosed. The nature of polymorphic markers is that they are variant structures, and in the present state of the art the structure (i.e. the nucleotide sequence) of one marker does not provide guidance to the existence or structure of other marker sequences. Furthermore, the knowledge of the tkt-hrcA region of variability in no way predicts other gene/extragenic combinations that are HPME since the nature of the sequences claimed is in fact that they are polymorphic in unpredictable ways from one species or genes or order of microbe to another. The genus Bifidobacterium genus has at least 47 different within it (Milani et al. 2016), and those taxa each can reasonably be expected to have within them polymorphism and variants. The disclosure in the specification in no way suggests the structure of the “marker” in each of these different organisms.
Further still, the specification does not describe any “microbial genome sequence” that is less than 2000 base pairs and comprises the required structures, consonant with the election of HPME for detection of the Bifidobacterium family. The genomic region in B. breve UCC2003 that contains both of the required genes is over 4000 base pairs in length (see GenBank DQ144724). That is, it is over 2000 base pairs. The specification does not teach any single HPME that meets all of the claim limitations, nor does it provide any guidance as to what “microbial genome sequence” does contain both required ORF, intervening promoter and is less than 2000 base pairs in length. The specification also fails to describe how a molecule of this length labeled with a detection means will be used to identify and quantify any organism.
The instant claims are drawn to a method for using genus of sequences which are identified not by their sequence structure but by their function. It is clear that the claims are attempting to encompass detecting sequences which are highly polymorphic relative to other sequences, but the structure of the claimed sequences are largely undefined. The genus from which the claimed sequences can be selected is enormous, considering the number of different bacteria contained within the Bifidobacterium family. The specification contemplates markers that can differentiate and identify genus, species, and subspecies but does not describe a single structure within the scope of the claims.
The specification at pages 32-33 and following disclose database accession numbers for a variety of different bacterial genomes. However, the disclosure does not identify which 2000 base pair or fewer sequences within these entire genomes are HPME within the scope of the claimed invention.
The disclosure fails to teach any art-recognized correlation between sequences which are markers for any species or organism in particular and any particular structure. Without any recognized correlation between structure and function, those of ordinary skill in the art would not be able to identify without extensive analysis and testing which sequences are within the scope of the claim and which are not. Thus, those of ordinary skill would not consider the applicant to have been in possession of the claimed methods for identifying and quantifying the genus of nucleic acids claimed.
There is no written description in the specification as to what specific features of a sequence would be characteristic of a “microbial sequence” nor are there known structural features taught in the prior art that would allow one skilled in the art to recognize a microbial sequence as such. The length limitation does not provide any guidance as to the contents of the sequence that is the marker.
Further, narrowing claims do not provide any specific structure either. The disclosure does not appear to provide a single example of the structure Highly Polymorphic and Modular Extragenic markers that meet the claim limitations, since none of the markers disclosed in the figures appear to comprise the required open reading frames, they only disclose partial open reading frames.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Ventura et al. (APPLIED AND ENVIRONMENTAL MICROBIOLOGY, Dec. 2005, p. 8998–9007) teaches characterization of the B. Breve hrcA locus. Figure 1 shows a diagram of the relationship between the tkt and hrcA genes. Nothing in the reference suggests amplifying the genomic region between these two regions with primers consisting of instant SEQ ID NO: 65 and 66.
A method for the detection of bifidobacterium which comprises amplifying a bacterial sample with primers consisting of SEQ ID NO: 65 and 66 would have written description and be free of the prior art. See Examples 7 and 11, and Table 7, p. 67. A claim of this scope would have the benefit of priority to the original PCT filing.
No prior art rejections are set forth at this time at least because the required region of the microbial genomic DNA set forth in the marker is longer than 2000 base pairs. The claims are logically inconsistent.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Juliet Switzer whose telephone number is (571)272-0753. The examiner can normally be reached Monday to Thursday, 8:00 AM-3:30 PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Winston Shen can be reached at (571)-272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Juliet Switzer
Primary Examiner
Art Unit 1682
/JULIET C SWITZER/ Primary Examiner, Art Unit 1682