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 II, species SEQ ID NO: 1 in the reply filed on 10/16/25 is acknowledged.
Claim Objections
Claims 21, 30, and 35 are objected to because they depend from withdrawn claim 16. The claim should be rewritten in independent form.
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 21-31 and 35 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 21, 30 and 35 are unclear when it recites a primer “according to” claim 16. This transitional phrase is unclear because it is uncertain if it means that the primer must meet all of the limitations set forth in claim 16 or if a primer “according to” allows for further variation, such as fragments of the sequences.
Claim 22 is unclear when it recites that the “nucleic acid is derived from” bacteria that belong to a human microbiome because it is not clear if this limits the source of the nucleic acid obtained in (a) and if so how or if the claim is trying to just limit the detection to bacteria that generally “belongs” to a human microbiome. Further, it is unclear what it means for nucleic acid to be “derived” from bacteria, does that mean they are isolated or extracted from bacteria or is something further required to accomplish the derivative? Claim 23 incorporates these limitations and is further indefinite for these reasons.
In claims 24 and 25, it is unclear if “derived from a swab” requires a specific step of obtaining a swabbed sample, or if “derived from a swab” has some other meaning such that additional steps are carried out to “derive” the sample from a swab.
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) 21-22, 26, 27, 28 and 35 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ao et al. US 9434999.
The reference teaches a method for amplifying part of the sequence of a Staphylococcus tuf gene, which comprises obtaining nucleic acid from bacteria of the genus Staphylococcus, amplifying the obtained nucleic acid with an oligonucleotide primer that comprises instant SEQ ID NO: 1. See Example 7, where SEQ ID NO: 15 in the reference comprises instant SEQ ID NO: 1. Instant SEQ ID NO: 1 is identical to nucleotides 3-21 of the prior art primer. Therefore, the reference anticipates instant claims 21 and 35.
With regard to claim 22, the reference teaches that the nucleic acid is isolated from bacteria in a blood culture sample, so the nucleic acid is derived from bacteria that belong to a human microbiome.
With regard to claim 26, the nucleic acid is DNA.
With regard to claim 27, the nucleic acid is amplified with a second primer that comprises “a complement” of SEQ ID NO: 2. The phrase “a complement” is extremely broad due the use of the indefinite article “a”. The second primer taught by the reference comprises 5’-gga-3’ at nucleotides 28-30 which are “a complement” of “tcc” which are nucleotides within instant SEQ ID NO: 2.
With regard to claim 28, the amplification is by PCR.
Claim(s) 21, 22, 26, 27, 28, 30, 31, and 35 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Heikens et al. (JOURNAL OF CLINICAL MICROBIOLOGY, May 2005, p. 2286–2290).
Heikens et al. teach a method which includes obtaining a nucleic acid, amplifying the obtained nucleic acid with a primer pair that targets the tuf gene, sequencing the amplified nucleic acid, comparing the sequences obtained in (c) with reference sequences from a plurality of Staphylococcus species and/or strains; and assigning the sequences obtained in (c) to a staphylococcus reference sequence, thereby identifying species and/or strains (See p. 2287, “PCR amplification” and “Gene Sequencing” and Table 3).
With regard to the limitation that the amplifying is with “at least one primer” according to claim 16, the primer of claim 16 comprises (c) “a” complement of (a) or (b). The use of the indefinite article “a” in this phrase results in an extremely broad claim construction where “a complement” can “a complement” of any length. And the recited primer must “comprise” this complement so the encompassed primer encompasses any primer that comprises “a complement” of any length of SEQ ID NO: 1 or 2 or sequences which is a least 85% identical to these.
The forward primer taught in the reference comprises “a complement” of SEQ ID NO: 1, namely nucleotides 5-7 of the TUF-F primer (5’-GTT-3’) are “a complement” of nucleotides 14-16 of instant SEQ ID NO: 1.
Regarding claims which require also a primer comprising “a complement” of SEQ ID NO: 2, nucleotides 16-18 of the primer TUF-R (5’-CTG-3’) is “a complement” of nucleotides 2-4 of instant SEQ ID NO: 2.
Therefore, the teachings of the reference anticipate claims 21, 27, 30, 31, and 35.
With regard to claim 22, the reference teaches that the nucleic acid is isolated from bacteria in a blood isolates from the neonatal intensive care unit, so the nucleic acid is derived from bacteria that belong to a human microbiome (i.e. is part of the complement of bacteria living in or on a human; See “Bacterial isolates”, p. 2287).
With regard to claim 26, the nucleic acid is DNA.
With regard to claim 28, the amplification is by PCR.
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(s) 21, 22, 23, 24, and 25 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ao et al. in view of Drinka et al. (Journal of the American Medical Directors Association. Volume 13, Issue 1, January 2012, Pages 75-79).
The teachings of Ao et al. as they address claims 21 and 22 are given previously in this Office action and are fully incorporated here. Ao et al. further teaches that sample types include swabs such as a nasal swab (Col. 8, line 16 and following), but do not teach amplification of nucleic acids obtained from a swab of skin or a human skin microbiome.
Ao et al. does not teach obtaining nucleic acid from a swab of skin, or a human skin microbiome. Here “skin microbiome” is broadly interpreted to include any bacteria colonizing or living on the surface of human skin.
Drinka et al. teaches swab cultures are probably the most commonly used method to determine the resistance pattern of skin pathogens treated in nursing home residents, including S. aureus, and that properly performed swab cultures could play an important role (Abstract and throughout).
It would have been obvious to have modified the method taught by Ao et al. by testing a swab culture as taught by Drinka et al. in order to identify bacterial present in the skin samples for the potential S aureus pathogen. One would have been motivated by the teachings of Ao et al. that certain swab samples are appropriate and the teachings of Drinka et al. that properly performed swab cultures could play an important role in the identification of methicillin resistant Staphylococcus.
Claim(s) 29 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ao et al. in view of Gulilat et al. (BMC Medical Genomics (2019) 12:81; 17 pages).
The teachings of Ao et al. as they address claims 21 are given previously in this Office action and are fully incorporated here. Ao et al. follows sequencing with target detection using a chip hybridization card assay (Example 7). Ao et al. does not teach sequencing the amplicon with next generation sequencing.
Gulilat teaches that targeted next generation sequencing as a tool for precision medicine. The reference teaches that it can serve as a comprehensive, rapid and reliable approach for the detection of sequence variants. It would have been prima facie obvious to have substituted next generation sequencing for the hybridization card assay taught by Ao et al. to achieve the predictable outcome of determining which targets were amplified in the sample. One would have been motivated to use sequencing instead of hybridization in order to obtain more complete and precise sequence information about the target.
Claim(s) 21, 22, 26, 27, 28, 29, 30, 31 and 35 is/are rejected under 35 U.S.C. 103 as being unpatentable over Heikens et al. (JOURNAL OF CLINICAL MICROBIOLOGY, May 2005, p. 2286–2290) in view of Van Reckem et al. (Microorganisms 2020, 8, 897; doi:10.3390/microorganisms8060897) and Martineau et al. (JOURNAL OF CLINICAL MICROBIOLOGY, July 2001, p. 2541–2547).
Heikens et al. teach a method which includes obtaining a nucleic acid, amplifying the obtained nucleic acid with a primer pair that targets the tuf gene, sequencing the amplified nucleic acid, comparing the sequences obtained in (c) with reference sequences from a plurality of Staphylococcus species and/or strains; and assigning the sequences obtained in (c) to a staphylococcus reference sequence, thereby identifying species and/or strains (See p. 4143, “tuf gene sequencing” and “Sequence analysis” and Table 1).
Heikens teaches that primers were designed by carrying out multiple sequence alignments, choosing highly conserved regions, and designing PCR primers from these regions. The primer pair used was designed to amplify a 412-bp-long fragment of the tuf gene.
Heikens et al. does not teach a method wherein the PCR is conducted using a primer as is recited in part (a) or (b) of claim 16. No claim currently requires this limitation, but this rejection is written against embodiments which are encompassed within the claims.
Van Reckem also teaches methods for amplifying and sequencing the Staphylococcus tuf gene.
Van Reckem teaches aligning 2566 publicly available tuf gene sequences of all staphylococcal species and developing a consensus sequence from the resulting multiple sequence alignment (p. 4 and Table S1). Van Reckem teaches developing three primer pairs intended for high-throughput sequencing and one primer set amplifying a larger part of the gene; See Table 2. Van Reckem teaches amplification of fragments followed by next generation sequences to identify the genus and species of the Staphylococcus (p. 6 and Figure 2).
Instant SEQ ID NO: 1 and 2 align together amplify a portion of the tuf gene that aligns to nucleotides 739-1208 of the Van Reckem consensus sequence.
The sequence of these primers is taught within the Van Reckem consensus sequence:
Instant seq id no 1:
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89
256
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Instant SEQ ID NO: 2
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86
342
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Greyscale
The primers taught by Heikens amplify a portion that amplifies nucleotides 693-1108 of the consensus sequence. The primers taught by Van Reckem amplify fragments of a variety of nucleotide lengths, producing amplicons of 301, 379, 307, and 869 in length.
Martineau also teaches a PCR assay for identification of Staphylococcus genus and species, and the method employs primers that amplify a fragment that is from nucleotides 742-1111 of the Van Reckem consensus. The forward primer of the Martineau method overlaps with instant SEQ ID NO: 1.
Both Heikins and Van Reckem teach routine methods of selecting primers, including aligning sequences of interest and selecting primers to amplified desired targets. Furthermore, Van Reckem teaches employing primers that are “degenerate” at positions that are variable among different species of Staphylococcus. All methods of amplification in the references, using all five primer pairs in the references are considered equally close prior art to instant claim 21.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to have modified the method taught by Heikens et al. so as to have carried out PCR amplification with additional primers selected from any set of primer pairs designed from the known Staphylococcus consensus sequence taught by Van Reckem element to detect the presence and allow species identification of Staphylococcus in a biological sample using the PCR and sequencing method taught by Heikens. An ordinary artisan would have been motivated to do so with a reasonable expectation of success, since: (i) Heikens and Van Reckem each taught designing useful oligonucleotide primers and probes from the known Staphylococcus tuf sequences, (ii) the complete consensus sequence representing 2566 different tuf gene sequences of all staphylococcal species was known in the art at the time of the invention, and (iii) the references demonstrate that a variety of different primer pairs are capable of functioning in nucleic acid amplification methods. Thus, absent any unexpected results with respect to the particular primers and probes recited in the claims, they are prima facie obvious in view of the combined teachings of the cited references.
Attention is also directed to KSR Int’l Co. v. Teleflex Inc. (550 U.S.____ , 127 S. Ct. 1727 (2007)) where the Supreme Court determined that “a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under § 103 (KSR, 550 U.S. at____ , 82 USPQ2d at 1397).”
In the instant case, as discussed above, an ordinary artisan would have been motivated to carry out methods for amplifying Staphylococcus tuf gene fragments from the known sequences for the detection and identification of Staphylococcus species as exemplified in the references. The complete nucleotide sequence of the consensus sequence of the tuf gene, which is disclosed in Van Reckem, presented the ordinary artisan with a finite number of possible primers for amplification. An ordinary artisan would have expected predictable results, and thus would have had a reasonable expectation of success, when testing the finite number of possible amplification primers and probes suggested by the combined references. Thus, the claimed method would have been obvious in view of the prior art.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Hwang teaches that the tuf gene sequence analysis has greater discriminatory power than 16S rRNA for identifying Coagulase-Negative Staphylococci, see Abstract and throughout.
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Juliet Switzer
Primary Examiner
Art Unit 1682
/JULIET C SWITZER/Primary Examiner, Art Unit 1682