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 .
Application Status
Amended claims 1-27 were filed on 3/13/2026 and are under consideration.
Any rejection or objection not reiterated herein has been overcome by amendment. Applicant’s amendments and arguments have been thoroughly considered but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Claim Rejections - 35 USC § 112(b)
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 11, 19, 20-22 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 11 is indefinite in the intent of the meaning of set of broad-taxonomic range amplification primers is a set of “universal bacterial amplification primers”. Applicant could intend to mean that the broad-range primers have universal amplification ability for bacteria, or applicant could intend a literal reference to what is conventionally understood to be universal primers, such as M13 or universal primers for ITS, such as ITS1F, or applicant may intend something different entirely. Further clarification is required. Notably, claim 24 depends from claim 11, but is definite because claim 24 discloses two sequences that are not found to be publicly available in the art.
Claim 19 is indefinite in the meaning of “essentially all strains or species” and essentially all strains ..from a microbial… Kingdom or Domain, since two ordinary artisans may come to different conclusions regarding what constitutes essentially all strains, and since it is markedly unclear how one would know when they had met the claim limitation of essentially all strains, from for example a Kingdom or Domain when the vast majority of microbes remain uncharacterized, since even within the human body, novel taxa are still being identified (Kowarsky et al 2017 114:9623-9628). Claims 20, 21, 22 depend from and are indefinite in claim 19.
Response to 35 USC § 112(b) Remarks of 3/13/2026:
Re: claim 11, Applicant remark’s point to the Declaration and state that use of broad taxonomic range primers is well known in the art, and that numerous publications described universal primers for 16S-23S rRNA ITS, and to refer to publications and Tables therein.
Response: ‘Universal primers’ differ by context, a point of the prior rejection. The claim recites a “set of universal bacterial amplification primers”. The specification uses universal liberally (see below). While known universal primers for bacteria exist for use in broad amplification in particular contexts, it is also well known in the art that different universal primers have different taxonomic coverage and bias. Here, the claim requires the functional property that the primer set be universal, but given the breadth of the claims (11 and 1), the scope of claim 11 is unclear in that the functional requirement for this set of broad-taxonomic range amplification primers that are universal primers could be to amplify all bacteria, or all of those within, or among, a given taxonomic grouping thus it remains unclear: universal, across what scope, being the issue.
The metes and bounds of universal in the specification are also not definitive.
Specification Pg 4, presents such that universal in general, is given a unique definition here: A more “universal” (applicant’s quotes) amplification of ..ITS instead of from species or strain specific sequence…Pg 4, the “universal” DNA amplification is preferably performed by using higher taxon level or group specific primers such as genus specific, family-specific…up to and/or domain specific…Pg 5, “Hitherto, such a universal PCR approach has not been applied in the clinic for microbial identification because such broad PCR amplification could result in the amplification of multiple PCR amplicons derived from multiple species…which does not result in actual identification in all situations”.
Pg 5, “Unexpectedly, the present inventor has found a way to make a universal PCR approach available for clinical use despite above mentioned problems by combining in said universal PCR approach two techniques that provide for a clinically sufficient sensitivity and specificity…
Pg 6. The presently claimed method provides for an assay that has a broad scope (i.e. many different micro-organisms can be detected e.g. universal bacterial)
Pg 13, In yet another preferred embodiment of an aspect of the invention, the set of broad-taxonomic range amplification primers is a set of universal bacterial amplification primers (…preferably comprising SEQID 14-15), where for example, SEQ ID 14-15 establish very clear bounds.
Re claim 19 (20-22), Applicant indicates “essentially all strains or species” is commonly used in biological sciences…and refers to their intent to “indicate coverage of a substantial majority of members of a taxonomic group” …rather than literal coverage of every existing strain and thus conveys a reasonably clear scope and renders the claim definite.
In reply, it is understood that biological sciences terminology may be used in claims with particularly understood meaning, however this terminology as used in this claim, does not render claim 1 definite. Applicant’s comments do not resolve the indefiniteness issue, and may in-fact contribute to the issue, stating that the expression indicates coverage of a substantial majority of members, another term that may also be considered indefinite.
Efforts to particularly define substantial majority in the dictionary result in a lack of definition for the term, and a need to combine two definitions such as “substantial” = considerable in quantity and majority as percentage of more than half (Merriam-webster). Cambridge does provide examples of use, including “In sharp contrast, a substantial majority (68%) rated the current …” (dictionary.cambridge.org/us/example/english/substantial-majority). When used in claims addressing recycling, substantial majority is disclosed as at least 60% (.law.cornell.edu/cfr/text/16) and this value, or “at least 51%” are recited by Law Insider (lawinsider.com/dictionary/substantial-majority).
Again, there is no definitive bound or objective measure in the claim, or a clear point when the public would recognize that they have infringed upon the claimed essentially all strains or species from a microbial genus, family, order class, phylum, kingdom and/or domain. This is particularly true and relevant in a claim such as claim 1 involving microorganisms, since among other issues, essentially all may change for a group and by default has associated ambiguity, given the massive amount of microorganismal diversity that is not yet categorized, and that is being categorized or will be in the near future, and since it is not objectively delimited what essentially all strains or species from a genus, family, order, class, phylum kingdom and/or domain actually entails. Also not clear, and of significant importance, is whether essentially all strains or species from a genus (say 97% of the genus) have the same bounds as essentially all strains or species from a Kingdom (then 97% of the Kingdom), or phylum, or other group. Further clarity is needed.
Claim Rejections - 35 USC § 112(a)
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.
Claim 1-27 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a Written Description rejection.
The MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Nature of the Invention:
The invention is directed to a method of microbial identification based upon DNA analysis, where Claim 1 recites “A method for identifying a microorganism at species or strain level in a biological sample by polymerase chain reaction (PCR), said method comprising the steps of: a) providing a biological sample suspected of comprising microbes, and optionally isolating nucleic acid sequences comprised in said biological sample; b) PCR amplifying at least one microbial rRNA internal transcribed spacer (ITS) region comprised in said, optionally isolated, nucleic acid sequences using a set of broad-taxonomic range amplification primers for amplifying said at least one microbial rRNA ITS, to thereby generate PCR amplicons; c) recording a high resolution melting curve for the PCR amplicons generated in step b), and recording the length of the PCR amplicons generated in step b) by capillary electrophoresis or sequencing; d) comparing the high resolution melting curve recorded in step c) with a database comprising high resolution melting curves of reference amplicons generated from reference microbial species or strains of known taxonomic identity using the same set of amplification primers, to thereby obtain a first taxonomic identity indicator of a microorganism present in said sample; e) comparing the length of each PCR amplicon having a distinct length recorded in step c) with a database comprising PCR amplicon lengths of reference amplicons generated from reference microbial species or strains of known taxonomic identity using the same set of amplification primers, to thereby obtain a second taxonomic identity indicator of a microorganism present in said sample; f) identifying a microorganism present in said sample to the species or strain level if the first and second taxonomic identity indicator match.”
Specifically relevant to this rejection, claim 1b addresses:
amplifying at least one microbial rRNA ITS region, using a set of broad-taxonomic range amplification primers for amplifying said at least one microbial rRNA ITS, to thereby generate PCR amplicons
This description encompasses a very large genus of primers, namely any primers that are capable of amplifying one or more microbial rRNA ITS regions, where the primers have a “broad-taxonomic range”, or wide range at a taxonomic level, which can be any taxonomic level.
State of Art: ITS primers have been widely used for many purposes, and notably, primers have been developed for multiple ITS regions in many taxa, though not so much for bacteria. Akhoundi et al (Molecular Aspects of Medicine, 57:1-29, 2017), addressed ITS use for leishmaniases studies, specifically considering species classification, and the sensitivity and specificity of markers to quantify variation from subgeneric levels (Abstract). Akhoundi pointed out that the most variable regions of rRNA genes, ideal for typing Leishmania species, are the ITS regions (Pg. 7 right col, 2nd full para, and final para). Cafarchia et al (Inf, Gen and Evol, 20:336-331, 2013) considered detection at the species level of pathogenic dermatophytic fungi of four Genus’ (Abstract). Here ITS use supported grouping by clinical traits, as well as species separation of geophilic species from other members of Arthrodermataceae (Pg 337 right col, final para; Table 2). Less common at the time of the filing was ITS use for bacterial species identification, though Andini (US20170321257 A1 published 11/9/2017) disclosed ITS primers for bacterial amplicon production [0006]. Thus, in sum, ITS primers are known in the literature, here used in line with the claims to identify species, but at this level, insufficient to be considered quite broad, particularly in line with the breadth of the claim. There is scant data regarding bacterial ITS amplification. Of significance as well, are the vast majority of microbes that we do not yet believe have been taxonomically identified. A fraction of this unknown volume is depicted in Kowarsky (PNAS 114: 9623-9628, 2017), who disclosed that even within human blood cell free DNA samples (inclusive of the microbes contained therein), many organisms (microbes and viruses) represent entirely novel taxa, just of the human microbiome alone (Abstract). Thus, we cannot necessarily even yet determine the entire Genus encompassed by all broad-taxonomic range amplification primers for rRNA ITS.
Guidance from Specification:
There is a Definitions section in the Specification (beginning on Pg 17), however “broad-taxonomic range” amplification primers are not defined.
Rather, the Specification disclosure on this topic is expansive:
Pg 4 addresses that ITS amplification is not species specific and Pg 5 states that universal DNA amplification for ITS can be at Genus, Family, Order, Phylum or Kingdom level.
On Pg 20, in an embodiment, these primers are for amplifying a microbial ITS region up to and including all strains or species from a Kingdom or Domain. However, “essentially all strains or species” preferably refers to more than 50%, up to 90+%, of species/strains in a genus, family, order, class, phylum, kingdom and/or domain. In another embodiment these primers are for at least one ITS region, amplifying 16S-23S rRNA ITS, then 23S-5S, and so on, with alternate regions.
Further “amplification primers” are defined broadly as “primers that hybridize to opposite strands of the target DNA sequence(s) and flank the region to be amplified”.
This description therefore is comprehensive, painted at high level of generality. The specification reveals SEQIDs for particular bacterial phyla (described below).
Specification Examples:
Example 1, prophetic, written in present/future tense at the start, addresses combining melting curves and 16S-23S IS fragment length data for species identification. The “high-level” writing lacking detail, indicates that DNA regions broadly conserved throughout taxonomical groups may be used when they have specific characteristics.
Example 1 continues with “strain selection and cultivation” which occurred for 12 bacterial species. The “DNA isolation” section disclosed exactly that; the “PCR” section disclosed phylum specific amplification of 16S-23S regions, with one SEQID for a forward primer targeting four Phyla: Firmicutes, Acintobacteria, Fusobacteria Verrucomicrobia, and another SEQID targeting one Phylum Bacteroidetes, plus three reverse primers providing universal coverage, SEQID 3-5, and additional primers with a subset of the aforementioned primers for the Proteobacteria phylum. The “third” PCR reaction mix was primers for a broad collection of bacteria, where the primer incorporated a suite of inosines to ensure broad reactivity.
Next, “species identification by melting curve analysis can be done…” was disclosed.
Next, “Fragment length analysis”; PCR, was performed with automated species calling by software linking peaks to IS-profile data for >500 microbial species.
Next, “Results” of melting curves and fragment analysis of eight species from three phyla (above), FIG3, where profiles are highly variable between species (Specification, Pg 40).
Example 2 addresses accurate identification for identical length fragments (e.g. similar melting curve or fragment length results for two species), Fig 4 depicts two different melting curves, or one comparison of two species, S pyogenes and C jeikeium.
Example 3 if the final example and addresses accurate identification when melting curves are the same, and reliance on 16S-23S fragment length profiles is discriminatory, and FIG5, depicts one comparison of two species, E. cloacae and K. pneumoniae.
Table1 lists a single forward primer for each Firmicutes and Bacterioidetes phyla, the 3 reverse primers (SEQID 1-5); a single forward primer for Proteabacteria Phylum and several reverse primers (SEQID 6-13). Next are one pair of primers described as universal bacterial ITS primers, with proline runs (SEQ ID 14-15).
What the disclosure does not teach:
There is no evidence of possession of the broad genus of primers that is any and all broad-taxonomic range amplification primers for amplifying said at least one microbial rRNA ITS, and which is also used also to meet additional relevant claim(s) limitations. This claim phraseology is much broader than the working examples depicting possession of one universal bacterial ITS primer set, three phyla-level bacterial primers that amplify <15 bacterial species, plus one comparison of two bacterial species distinguished by amplicon melting and one comparison of two bacterial species distinguished by fragment length.
Thus, a small subset of amplified bacterial species, of phyla, and of the range of 16S-23S for ITS, present evidence of possession of a fraction of this large, claimed genus of primers, but lacking is the breadth and variety that would encompass any and all broad-taxonomic range primers.
Conclusion: Taking into consideration the factors outlined above, including the nature of the invention, the state of the art, the limited guidance provided by the applicant and the specific example, it is concluded that Applicant does not indicate possession of the broad Genus of primers of the invention, as described.
Response to 35 USC § 112(a) Remarks of 3/13/2026 and Declaration:
Remark: Applicant remarks indicate that the PCR amplification of Claim 1b is routine and well-established, that broad range amplification of ribosomal ITS has been long described, that the specification provides specific primer examples including phylum specific primer sets, which is sufficient to demonstrate possession, and the Examiner too narrowly interprets the claimed genus of primers and underestimates knowledge in the field.
Response: As the above Remark summarizes the more detailed Declaration, more comprehensive replies will be found after the Declaration statements. In brief, a few disclosed genus-level primers and knowledge in the art remain insufficient to demonstrate that applicant possesses the breadth of the invention as claimed.
Declaration (section 4): indicates that Applicant is in possession of invention and the method step of amplifying ITS using broad taxonomic range amplification primers is well known in ribosomal DNA-based assays.
The Declaration (section 7) references the Specification “Background” to indicate where this is demonstrated, and points to use of untargeted or broad-range detection for clinical samples. Applicant points to Specification Page 4 where the approach combined ‘less-specific amplification protocols with specific ones’, such that the claimed method provides “for an assay that has a broad scope ‘(i.e. many different microorganisms can be detected e.g. universal bacterial).
Further, it is stated (section 8) that broad amplification is well known in the art and originates in recognition of conserved sequences…that are primer annealing sites. Thus conserved and variable regions are useful in designing probes.
References are cited addressing variable ITS spacer in bacterial ribosomal operon (Garcia-Martinez, Gurtler and Stanisich, Fisher and Triplett). Reference is made to Garcia-Martinez, Table 1, with universal primers, and discussion of how probes could be made discriminative at several taxonomic levels, and that particular bacterial communities can be amplified. Fisher and Triplett amplify from a bacterial community. The section ends with the fact that the use of broad taxonomic range primers has been known for over 30 years.
Section 9. indicates that claim 1 is routine, in broad-taxonomic range detection methods.
Section 10. cites the examiner stating there is scant data regarding ITS amplification for bacteria, particularly bacterial species identification. The section reiterates 30 years of ITS use in bacteria and use of the term broad range nucleic acid amplification.
Andini is addressed as using the term broad-range, which is indicated to be common in the art.
Sections 11-21 address fragments, melting curves, and analysis, and pertain more to the 103 rejection.
Response:
The Declaration provides examples from the art and relevant additional facts that pertain to multiple relevant issues (use terms and ITS) and are pertinent to addressing the 103 rejection and thus is clearly more than merely conclusory. However, the Declaration does not demonstrate possession of the invention as claimed. For example, while the specification recites primers it does not articulate why these represent the full scope of ‘broad taxonomic range amplification primers. They do not, thus there is not demonstration of possession of the entire breadth of the claimed genus.
Reference in the Declaration, to the Background of the Specification is of value in that the section referred to appears to consider a subset of all extant microorganisms, referencing detection of clinical samples, which is anticipated to be substantially narrower in scope than the breadth of the claims, encompassing any microorganism species’ that may be amplified with primers for ITS that may amplify multiple strains/species from a taxonomic level as broad as Kingdom or Domain (Pg 11, end),
While it is understood that “less specific” and more specific amplification protocols are in use for claim 1 however, the e.g. “universal bacterial” is not understood by the Examiner.
Reference to the art (including e.g. Garcia-Martinez, Table 1) does define known universal primers (~10) and also comments that primer design does depend on the organisms and use and discusses use in community fingerprinting (Pg 57 right col, final para). Notably, the studies considered are not addressing any and all microbes, but rather a subset, in a context (a particular ecosystem, e.g. an aquatic (seawater) community, and soil-based examples (Pg 60 right col, Pg 61 left col) are two disclosed by Garcia-Martinez, where the work was conducted by Boneman and Triplett (1997), who disclose one universal primer that Garcia-Martinze, Table 1, indicate is used in Archaea and Bacteria Domains. Two more are found in Table 1, used in Archaea, Bacteria, though further detail is absent. Garcia Martinez does address the high variability
What was much less typical was amplification of any and all species/strains at the Domain or Kingdom level, with a set of broad-taxonomic range amplification ITS primers, per claim 5. Possession of these broad-taxonomic range amplification primers was not identified in the Specification.
The examiner statement should not have been so ‘strong’ as to say primers for ITS were developed in many taxa though not so much for bacteria, for which there was scant data, and should have completed the thought which related to use in bacterial species relative to other taxa (e.g. fungi). It is, for example, the breadth of the term broad-taxonomic range amplification primers, that are said to amplify ITS from multiple strains at Domain level for which possession is absent.
Reference to Andini is insufficient to indicate possession of the breadth of the claims. Sufficient description of a representative number of species in the Specification satisfying the requirement of a claimed Genus by reduction to practice is not met for the breadth of the claims as recited, given that there are not a representative number of species disclosed in the Specification, nor is the breadth of the array of taxonomic levels supported. This is true, even independent the large array of unidentified bacteria that may lend unpredictability to primer functionality or amplification success. The rejection points out the extremely broad scope of taxonomic range of primers and amplification that are allowed by the claim, which contrasts with the Specification and even with the art presented in the Disclosure.
The arguments do not overcome the rejection because they rely too heavily on the knowledge of one of ordinary skill and art, rather than explicitly demonstrating possession of functional broad-taxonomic range primers that provide for amplification, beyond Phyla level, for any and all microbial species/strains, as a compensatory measure for conveying possession of the full breadth of the claimed genus, when the disclosure does not provide ample or sufficient description/reduction to practice of the invention as claimed.
The Declaration does not truly identify where in the originally filed Specification there is demonstration of possession of the full scope of the claimed genus of the set of such broad taxonomic range amplification primers. The arguments/Declaration have been carefully considered and while valuable support for the 35 USC § 103 rejection, are insufficient to overcome the 35 USC § 112(a) rejection.
Conclusion
All claims are rejected.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Lisa Horth whose telephone number is (703)756-4557. The examiner can normally be reached Monday-Friday 8:30-4:30 EST.
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/LISA HORTH/ Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
Prosecution Insights