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 .
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Summary
Claims 2, 5-7, 11-12, 18, 21, 23-24, 27, 29, 31-32, 36-37, and 100 have been amended. Claims 3-4, 8-10, 13-17, 19-20, 22, 25-26, 28, 30, 33-35, 38, 40-68, 70-99, and 101-102 have been canceled. Claims 1-2, 5-7, 11-12, 18, 21, 23-24, 27, 29, 31-32, 36-37, 39, 69, and 100 are pending. Claims 1-2, 5-7, 11-12, 18, 21, 23-24, 27, 29, 31-32, 36-37, 39, 69, and 100 are under examination and discussed in this Office action.
Drawings
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (see pages 1-4, and 41). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of terms such as Cepheid Xpert (see page 6 of the specification) and Cobas (see page 47 of the specification), which are trade names or marks used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
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 2, 5-7, 12, 18, 23-24, 27, 29, and 31- 32 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 2 recites the limitation "wherein the agent lyses the cells”. There is insufficient antecedent basis for this limitation in the claim. “The cells” have not been earlier introduced in the claims, and because of this it is further unclear what cells are being referred to, such as patient cells or bacterial cells. For the purpose of compact prosecution, “the cells” are interpreted to mean patient cells and/or bacterial cells.
Claim 5 recites the limitation “wherein the crRNA is complementary to a nucleic acid sequence of a target gene”. It is unclear from this recitation which crRNA the claim is referring to as two crRNA’s are introduced in claim 1: a crRNA comprising a nucleic acid sequence that is complementary to a nucleic acid sequence of Chlamydia trachomatis and a crRNA comprising a nucleic acid sequence that is complementary to a nucleic acid sequence of Neisseria gonorrhoeae. It is further unclear, if there was not intended to be two different crRNA’s, how one crRNA could be complementary to both target genes that are claimed. For the purpose of compact prosecution, the above recited limitation is interpreted as the crRNA comprising a nucleic acid sequence that is complementary to a nucleic acid sequence of Chlamydia trachomatis and the crRNA comprising a nucleic acid sequence that is complementary to a nucleic acid sequence of Neisseria gonorrhoeae are each complementary to a nucleic acid sequence of a target gene in their respective organisms.
Claim 6 recites the limitation "the first single stranded linker probe comprises a nucleic acid sequence of the target gene of Chlamydia trachomatis and the second single stranded linker probe comprises a nucleic acid sequence of the target gene of Neisseria gonorrhoeae". There is insufficient antecedent basis for this limitation in the claim. Claim 1, from which claim 6 depends, does not introduce a target gene for Chlamydia trachomatis or a target gene for Neisseria gonorrhoeae. Claim 7 is also rejected here for its dependence on claim 6 and not clarifying the identified issue.
Claim 7 recites the limitation "wherein the crRNA that is complementary to cryptic plasmid ORF6 segment sequence…wherein the crRNA that is complementary to major outer membrane protein porB sequence…". There is insufficient antecedent basis for this limitation in the claim. Claims 1 and 6, from which claim 7 depends, do not introduce the crRNA that is complementary to cryptic plasmid ORF6 or the crRNA that is complementary to major outer membrane protein porB. These are introduced in claim 5.
Claim 12 recites the limitation “wherein the single stranded nucleic acid linker probe of part ii) comprises SEQ ID NO:5, wherein the single stranded nucleic acid linker probe of part iv) comprises SEQ ID NO:17”, and further depends from the method as described in claim 1. In certain embodiments, it is unclear how the use of these specific ssDNA linker probes will successfully discriminate between Chlamydia trachomatis and Neisseria gonorrhoeae. For instance, if the CRISPR nuclease of claim 1 is embodied as a single CRISPR nuclease of Cas12a, it is unclear how Cas12a will specifically collaterally cleave SEQ ID NO:5 or SEQ ID NO:17 if only one bacteria is present in a sample because Cas12a is not known to collaterally cleave specific sequences. Kellner (SHERLOCK: nucleic acid detection with CRISPR nucleases, Nature Protocols, September 2019, 14, 2986-3012) teaches that Cas12a is not known to have a collateral cleavage motif preference and instead has nonspecific nuclease activity towards ssDNA (Page 2986, paragraph 1; Box 1: motif preference not applicable; Figure 2, multiplex detection, Cas12a has no specific collateral cleavage motif). Given these considerations, a multiplex detection of Chlamydia trachomatis and Neisseria gonorrhoeae will result in both ssDNA linker probes being cleaved even if only one bacteria is present in the sample. The activated Cas12a will indiscriminately collaterally cleave any ssDNA in the reaction, resulting in a false positive test for at least one of the bacteria. Therefore, in some embodiments, it is unclear how claim 12 will work as claimed.
Claim 18 recites the limitation “wherein the first, second, third and/or fourth single stranded nucleic acids are bound to one or more labels, wherein the label is selected from any one of a fluorescent label, radiolabel, streptavidin, an antibody, 6-carboxyfluorescein (FAM), biotin, a thiol group located on the 5' or 3' end of the single stranded nucleic acid, a nanoparticle, and combinations thereof”. It is unclear from this recitation if all the single stranded nucleic acids are intended to be bound together to the same label or labels, or if they can each individually be bound to a different label or labels. It is also unclear if the different label is the same type of label for each individual single stranded nucleic acid, or if a different label can be used for each individual single stranded nucleic acid. This is further complicated by the recitation of “the label is selected from…”, which could be interpreted as there being only one label that is used for all of the individual single stranded nucleic acids, eliminating the option for more. For the purpose of compact prosecution, the above cited limitation will be given the broadest reasonable interpretation of the single stranded nucleic acids being bound to one or more labels, wherein this can include all single stranded nucleic acids being individually bound to the same type of label. Claims 27 and 32 are also rejected here for their dependence on claim 18 and not further clarifying the identified issue.
Claim 23 recites the limitation “wherein a single gold nanoparticle is bound to multiple single stranded nucleic acids.” It is unclear from this recitation whether the first through the fourth single stranded nucleic acids are all bound to a single gold nanoparticle, or if there are multiple of each single stranded nucleic acid bound to individual gold nanoparticles. If more than one of the first through the fourth single stranded nucleic acid are bound to the same gold nanoparticle, it is then unclear how the gold nanoparticle would differentiate between detecting Chlamydia trachomatis and Neisseria gonorrhoeae. Turning to the specification, page 34, lines 18-19, state that a single gold nanoparticle can be bound to more than one single stranded nucleic acids of the same sequence, or of different sequences. For the purpose of compact prosecution, the above cited claim recitation will be interpreted based on the citation provided from the specification.
Claim 24 recites the limitation “wherein the complex comprising the single stranded nucleic acid linker probes of parts ii) and/or iv) hybridized to the single stranded nucleic acids form agglomerates”. There is insufficient antecedent basis for this limitation in the claim. Claim 1, from which claim 24 depends, does not recite the single stranded nucleic acids, but instead a first, second, third, and fourth single stranded nucleic acid. This further makes it unclear whether the linker probes are intended to hybridize to all four of the single stranded nucleic acids, or to the single stranded nucleic acids as specified in claim 1. For the purpose of compact prosecution, the above cited limitation is interpreted as wherein the complex comprising the single stranded nucleic acid linker probe of part ii) and the first and second single stranded nucleic acids and/or the single stranded nucleic acid linker probe of iv) and the third and fourth single stranded nucleic acids form agglomerates.
Claim 29 recites the limitation "further comprising loading the sample comprising the single stranded linker probes and the single stranded nucleic acids". There is insufficient antecedent basis for this limitation in the claim. Claim 1, from which claim 29 depends, does not recite the single stranded linker probes and the single stranded nucleic acids, but instead a first single stranded linker probe and a second single stranded linker probe, as well as a first, second, third, and fourth single stranded nucleic acid. Neither the linker probes, nor the single stranded nucleic acids, have been referred to as a group previously. Claim 29 also recites “loading…onto a lateral flow assay to detect the presence or absence of the complex”. It is unclear from this recitation how to load samples onto an assay without acknowledging what specifically the sample is being loaded onto. For instance, the sample may actually be loaded onto a lateral flow assay strip, but as currently claimed, the sample could be loaded onto any surface of the lateral flow assay. Loading onto any surface besides the reaction surface would not give any kind of result from the assay. For the purpose of compact prosecution, the above cited recitation is interpreted as loading onto a lateral flow assay strip. Claim 31 is also rejected here for its dependence on claim 29 and not further clarifying the identified issue.
Claim 32 recites the limitation "wherein an antibody is added to the sample that binds to one or more labels on the single stranded nucleic acid". There is insufficient antecedent basis for this limitation in the claim. Claims 1 and 18, from which claim 32 depends, introduce four different single stranded nucleic acids. Therefore, there is no basis for “the single stranded nucleic acid” and it is unclear what labelled single stranded nucleic acid the antibody is intended to bind to. For the purpose of compact prosecution, the above recited limitation will be interpreted to mean an antibody binds to the one or more labels on the first, second, third, and/or fourth single stranded nucleic acids.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 23 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to include all the limitations of the claim upon which it depends. Claim 23 as currently written depends from claim 20, which has been cancelled. Therefore, as currently written it does not depend from any other claim and thus fails to include all limitations of the claim upon which it depends. Applicant may cancel the claim, amend the claim to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements. For the purpose of compact prosecution, claim 23 will be interpreted to depend from claim 21, given the prosecution history related to claim amendments wherein claim 23 at one point depended from claim 20 or claim 21.
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.
Scope of Enablement
Claims 1-2, 5-7, 11-12, 18, 21, 23-24, 27, 29, 31-32, 36-37, 39, 69, and 100 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 a human subject, does not reasonably provide enablement for any subject as embraced by the claims. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.” See MPEP § 2164. These factors include, but are not limited to: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The office has analyzed the specification in direct accordance to the factors outlines in In re Wands. MPEP 2164.04 states: “[W]hile the analysis and conclusion of a lack of enablement are based on factors discussed in MPEP 2164.01(a) and the evidence as whole, it is not necessary to discuss each factor in written enablement rejection.” These factors will be analyzed, in turn, to demonstrate that one of ordinary skill in the art would have had to perform “undue experimentation” to make and/or use the invention and therefore, applicant’s claims are not enabled.
(A) With respect to the breadth of the claims: Claim 1 as currently drafted encompasses a method for detecting Chlamydia trachomatis and Neisseria gonorrhoeae in a sample from a subject using CRISPR. “A subject” and “the subject” does not limit the subject to a human subject as described in the specification. Consequently, the breadth of the claims is expansive since they encompass any kind of non-human subject. This can include subjects such as dogs, cats, and birds, among many other examples. Claims 2, 5-7, 11-12, 18, 21, 23-24, 27, 29, 31-32, 36-37, 39, 69, and 100 encompass the same breadth as claim 1 since they do not limit the subject to a human subject.
(B) The nature of the invention: The invention is in the field relating to infectious diseases, in particular sexually transmitted infections and methods of their detection and treatment.
(C), (D), (E) With respect to the state of the prior art, the level of one of ordinary skill and predictability of the art: Juppner (Functional properties of the PTH/PTHrP receptor, Bone, August 1995, S39-S42) teaches that despite significant structural conservation, rat, opossum, and human PTH/PTHrP receptor homologs display distinct functional characteristics (Abstract; Pages 39S-40S). This art indicates that there is known functional differences between homologs in different organisms, and therefore inter-species extrapolation would be unpredictable.
The art supports use of specific subjects. However, methods comprising any subject are highly unpredictable.
The invention is drawn to biological molecules, and is therefore in a class of invention which the CAFC has characterized as “the unpredictable arts such as chemistry and biology.” Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001). The level of skill in the art is therefore deemed to be high.
(F), (G) With respect to the amount of direction and working examples provided by the applicant: While the Applicant has provided description of a subject including a human or non-human animal (Page 20, lines 5-9), the working examples provided by the Applicant are directed to only human subjects. As noted at Page 4, lines 24-26; Page 45, lines 4-9; Page 47, Table 1; and Figure 1, for example, the samples used in the working examples are clinical samples from humans. The Applicant has not provided working examples directed towards any other type of subject.
(H) Undue experimentation would be required to practice the invention as claimed due to the amount of experimentation necessary because of the expansive breadth of the claims, the state of the prior art and its high predictability, and the limited amount of guidance in the form of varied working examples in the specification. A skilled artisan recognizes that a subject very broadly refers to any number of different species and thus applicability of the claimed method to a subject as embraced by the claims remains unpredictable, requiring undue experimentation. For example, an artisan would need to test the method on an expansive number of different organisms to determine if it is applicable to detection of Chlamydia trachomatis and/or Neisseria gonorrhoeae in said organisms. This reasonably represents undue experimentation.
MPEP §2164.01(a), 4th paragraph, provides that, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1157, 1562; 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
Genentech Inc. v. Novo Nordisk A/S, 42 USPQ2d 1001, 1005 (CA FC), states that, “[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable,” citing Brenner v. Manson, 383 U.S. 519, 536 (1966) (stating, in the context of the utility requirement, that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion”). The Genentech decision continued, “tossing out the mere germ of an idea does not constitute enabling disclosure. While every aspect of a generic claim certainly need not have been carried out by an inventor, or exemplified in the specification, reasonable detail must be provided in order to enable members of the public to understand and carry out the invention.” Id. at p. 1005.
After applying the Wands factors and analysis to claims 1-2, 5-7, 11-12, 18, 21, 23-24, 27, 29, 31-32, 36-37, 39, 69, and 100, in view of the applicant’s entire disclosure, and considering the In re Wright, In re Fisher and Genentech decisions discussed above, it is concluded that the practice of the full scope of the invention as claimed would not be enabled by the written disclosure. Therefore, claims 1-2, 5-7, 11-12, 18, 21, 23-24, 27, 29, 31-32, 36-37, 39, 69, and 100 are rejected under 35 U.S.C. §112(a) for failing to disclose sufficient information to enable a person of skill in the art to practice the claimed invention to it the full scope embraced by the claims.
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.
Claim 100 is rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon without significantly more. While the claim is directed to a process, and therefore meet step 1 of the subject matter eligibility test (see MPEP 2106.03), the claim(s) recite the natural correlation between the presence of Chlamydia trachomatis and/or Neisseria gonorrhoeae and infection, followed by non-specific treatment. Such correlation is a natural phenomenon because it describes a consequence of natural processes in the human body (e.g. presence of Chlamydia trachomatis and/or Neisseria gonorrhoeae infection).
Step 2A of the subject matter eligibility test requires a two-pronged analysis. Prong One asks: does the claim recite an abstract idea, law of nature or natural phenomenon? As discussed in MPEP 2106.04(II)(A)(1), the meaning of “recites” is “set forth” or “describes”. That is, a claim recites a judicial exception when the judicial exception is “set forth” or “described” in the claim. In the instant case, the claims describe a natural phenomenon: the natural correlation between the presence of Chlamydia trachomatis and/or Neisseria gonorrhoeae and infection.
Prong Two of the analysis under step 2A asks: does the claim recite additional elements that integrate the judicial exception into a practical application of the judicial exception? As discussed in MPEP 2106.04(II)(A)(2), “Because a judicial exception is not eligible subject matter, Bilski, 561 U.S. at 601, 95 USPQ2d at 1005-06 (quoting Chakrabarty, 447 U.S. at 309, 206 USPQ at 197 (1980)), if there are no additional claim elements besides the judicial exception, or if the additional claim elements merely recite another judicial exception, that is insufficient to integrate the judicial exception into a practical application. See, e.g., RecogniCorp, LLC v. Nintendo Co., 855 F.3d 1322, 1327, 122 USPQ2d 1377 (Fed. Cir. 2017) ("Adding one abstract idea (math) to another abstract idea (encoding and decoding) does not render the claim non-abstract"); Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016) (eligibility "cannot be furnished by the unpatentable law of nature (or natural phenomenon or abstract idea) itself."). For a claim reciting a judicial exception to be eligible, the additional elements (if any) in the claim must "transform the nature of the claim" into a patent-eligible application of the judicial exception, Alice Corp., 573 U.S. at 217, 110 USPQ2d at 1981, either at Prong Two or in Step 2B.” The considerations to be used are set forth at MPEP 2106.05(a) through (c) and (e) through (h). Turning to those sections of the MPEP:
MPEP 2106.05(a) has to do with improvements to the functioning of a computer or to any other technology or technical field. The claims at issue do not improve the functioning of a computer or other technology. While the instant claims recite steps of detecting Chlamydia trachomatis and Neisseria gonorrhoeae in a sample from a subject using a CRISPR method to determine the presence or absence of the bacteria, and administering a generic treatment to treat a Chlamydia trachomatis and/or Neisseria gonorrhoeae infection, the claims do not improve upon CRISPR methods or administration of treatment. The claims merely use existing methods for these steps. Note that “[u]sing well-known standard laboratory techniques to detect enzyme levels in a bodily sample” is an example that the courts have indicated may not be sufficient to show an improvement to technology.
MPEP 2106.05(b) has to do with whether the claims involve the use of a particular machine. In this case, the claims do not involve the use of a particular machine. While the instant claims recite steps of detecting Chlamydia trachomatis and Neisseria gonorrhoeae in a sample from a subject using a CRISPR method to determine the presence or absence of the bacteria, and administering a generic treatment to treat a Chlamydia trachomatis and/or Neisseria gonorrhoeae infection, no such machines are required by the claim, and certainly no particular machines. Even if some conventional machine were recited in the claims, like a heat block to heat the CRISPR reaction, further considerations such as the particularity or generality of the recited machine must be taken into account, as well as whether the involvement of the machine is merely extra-solution activity. MPEP 2106.05(g) describes “extra-solution activity”, noting that “[d]etermining the level of a biomarker in blood” is an example of “mere data gathering” which the courts have found to be insignificant extra-solution activity.
MPEP 2106.05(c) has to do with whether the claims involve a particular transformation. Here, none of the limitations of the claims involve a particular transformation. For example, while cleavage of nucleic acids by a CRISPR nuclease does result in smaller strands of nucleic acids, this does not transform those nucleic acids into something other than nucleic acids.
MPEP 2106.05(e) has to do with “other meaningful limitations”. The additional limitations imposed upon the natural correlation between the presence of Chlamydia trachomatis and/or Neisseria gonorrhoeae and infection in the instant case have to do with detecting Chlamydia trachomatis and Neisseria gonorrhoeae in a sample from a subject using a CRISPR method to determine the presence or absence of the bacteria, and administering a generic treatment to treat a Chlamydia trachomatis and/or Neisseria gonorrhoeae infection. These limitations are not considered “meaningful limitations”. MPEP 2106.05(e) states: “The phrase "meaningful limitations" has been used by the courts even before Alice and Mayo in various contexts to describe additional elements that provide an inventive concept to the claim as a whole.” However, as will be discussed below, these limitations do not arrive at an inventive concept. In addition, as has been discussed, they represent insignificant extra-solution activity, i.e. “data gathering”.
MPEP 2106.05(f) raises the question as to whether the additional elements recited in the claim represent “mere instructions to apply an exception”. Here, the judicial exception is the natural correlation between the presence of Chlamydia trachomatis and/or Neisseria gonorrhoeae and infection. The additional elements recited in the claims (i.e. detecting Chlamydia trachomatis and Neisseria gonorrhoeae in a sample from a subject using a CRISPR method to determine the presence or absence of the bacteria, and administering a generic treatment to treat a Chlamydia trachomatis and/or Neisseria gonorrhoeae infection) does amount to mere instructions to apply the correlation, since the collection of samples and CRISPR reactions serve as mere conventional steps taken for the purpose of gathering data to determine there is a Chlamydia trachomatis and/or Neisseria gonorrhoeae infection that needs treatment, which any practical use of the natural correlation would require.
MPEP 2106.05(g) has to do with whether the additional elements of the claim amount to insignificant extra-solution activity. MPEP 2106.05(g) notes that “[d]etermining the level of a biomarker in blood” is an example of “mere data gathering” which the courts have found to be insignificant extra - solution activity. Likewise, MPEP 2106.05(g) notes that “[p]erforming clinical tests on individuals to obtain input for an equation” also represents insignificant extra-solution activity. This aligns closely with the instant claims, where the additional elements of the claims amount to gathering samples, detecting Chlamydia trachomatis and Neisseria gonorrhoeae in a sample from a subject using a CRISPR method to determine the presence or absence of the bacteria, and administering a generic treatment to treat a Chlamydia trachomatis and/or Neisseria gonorrhoeae infection.
MPEP 2106.05(h) has to do with whether the additional elements amount to more than generally linking the use of a judicial exception to a particular technological environment or field of use. Here, the recitation of the field of the invention relating to infectious diseases, in particular sexually transmitted infections and methods of their detection and treatment. However, as MPEP 2106.05(h) indications, such limiting to a particular “field of use” does not confer patentability on otherwise ineligible subject matter.
In addition, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception (as set forth in step 2B of the subject matter eligibility test; see MPEP 2106-III) because it was known in the prior art to use CRISPR methods as claimed, detect specifically Chlamydia trachomatis and Neisseria gonorrhoeae with a CRISPR method, and to treat Chlamydia trachomatis and/or Neisseria gonorrhoeae infections.
Yuan (Universal and Naked-Eye Gene Detection Platform Based on the Clustered Regularly Interspaced Short Palindromic Repeats/Cas12a/13a System, Analytical Chemistry, February 2020, 92, 4029-4037) teaches a method of detecting bacteria in a sample, comprising providing the sample (Page 4033, column 2, paragraph 3 to Page 4034, column 1, paragraph 1; Figure 4; Page 4031, column 1, paragraph 3; Figure 1); contacting the sample with i) a complex comprising a CRISPR nuclease having collateral nuclease activity and a crRNA comprising a nucleic acid sequence complementary to a nucleic acid sequence of a bacteria of interest (Page 4033, column 2, paragraph 3 to Page 4034, column 1, paragraph 1; Figure 4; Page 4031, column 1, paragraph 3; Figure 1); and ii) a first single stranded nucleic acid linker probe (Page 4033, column 2, paragraph 3 to Page 4034, column 1, paragraph 1; Figure 4; Page 4031, column 1, paragraph 3; Figure 1); d. incubating the sample with the complexes of parts i) and single stranded linker probes of parts ii) for a period of time (Page 4033, column 2, paragraph 3 to Page 4034, column 1, paragraph 1; Figure 4; Page 4031, column 1, paragraph 3; Figure 1); wherein when the nucleic acid sequence of the bacteria of interest is present in the sample, the collateral nuclease activity of the complex of part i) is activated and the first single stranded nucleic acid linker probe of part ii) is cleaved by the nuclease (Page 4033, column 2, paragraph 3 to Page 4034, column 1, paragraph 1; Figure 4; Page 4031, column 1, paragraph 3; Figure 1); wherein when the nucleic acid sequence of the bacteria of interest is not present in the sample, the collateral nuclease activity of the complex of part i) is not activated and the first single stranded nucleic acid linker probe of part ii) is not cleaved (Page 4033, column 2, paragraph 3 to Page 4034, column 1, paragraph 1; Figure 4; Page 4031, column 1, paragraph 3; Figure 1); contacting the sample with a first single stranded nucleic acid that hybridizes to a first nucleic acid sequence of the first single stranded nucleic acid linker probe of part ii) and a second single stranded nucleic acid that hybridizes to a second nucleic acid sequence of the first single stranded nucleic acid linker probe of part ii) (Page 4033, column 2, paragraph 3 to Page 4034, column 1, paragraph 1; Figure 4; Page 4031, column 1, paragraph 3; Figure 1); wherein the first and second single stranded nucleic acids hybridize to the first single stranded nucleic acid linker probe of part ii) when the first single stranded nucleic acid linker probe of part ii) is not cleaved, to form a complex comprising the first single stranded nucleic acid linker probe of part ii) and the first and second single stranded nucleic acids (Page 4033, column 2, paragraph 3 to Page 4034, column 1, paragraph 1; Figure 4; Page 4031, column 1, paragraph 3; Figure 1); detecting the presence or absence of the complex comprising the first single stranded nucleic acid linker probe of part ii) hybridized to the first and second single stranded nucleic acids, thereby detecting the presence or absence of nucleic acid from the bacteria of interest in the sample (Page 4033, column 2, paragraph 3 to Page 4034, column 1, paragraph 1; Figure 4; Page 4031, column 1, paragraph 3; Figure 1). Yuan teaches the detection system can be either a Cas12a system or a Cas13a system (Page 4031, column 1, paragraphs 3-4; Figure 1). Yuan teaches that these systems use different linker nucleic acids: ssDNA for Cas12a (Page 4031, column 1, paragraphs 3; Figure 1) and ssRNA for Cas13a (Page 4031, column 1, paragraphs 4; Figure 1). Yuan teaches that Cas13a may also be used to detect bacteria (Page 4034, column 2, paragraph 2 to Page 4035, column 1, paragraph 1; Figure 6). Yuan teaches that samples may come from actual subjects, obviating this variation (Page 4033, column 1, paragraph 2).
Zhang (US 20210108267A1) teaches that two CRISPR systems comprising Cas12 and Cas13 may be used in multiplex to detect multiple targets of interest, given the different trans-cleavage targets of Cas12 (ssDNA) and Cas13 (ssRNA) (Page 1, paragraphs [0006]-[0007]). Zhang teaches that these targets may be Chlamydia trachomatis and Neisseria gonorrhoeae (Pages 47-48, paragraph [0484]).
Yonke (Chlamydial and Gonococcal Infections: Screening, Diagnosis, and Treatment, American Family Physician, April 2022, 105, 388-396) teaches on treating an infection caused by Chlamydia trachomatis and/or Neisseria gonorrhoeae (Page 392, column 2, paragraph 3) after detection with nucleic acid amplification techniques (Page 391, column 2, paragraph 2 to Page 392, column 1, paragraph 1).
Having considered the factors discussed in MPEP 2106.05 (a)-(c) and (e)-(h), as well as the prior art of Yuan, Zhang, and Yonke, it is clear that the additional elements recited in the claims, whether considered individually or as a combination, do not integrate the judicial exceptions into a practical application of those exceptions in such a way as to provide meaningful limits on the use of the judicial exceptions. Therefore, claim 100 is rejected here under 35 U.S.C. 101.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2, 11, 18, 21, 23-24, 27, 29, 31-32, 39, and 69 are rejected under 35 U.S.C. 103 as being unpatentable over Yuan (Universal and Naked-Eye Gene Detection Platform Based on the Clustered Regularly Interspaced Short Palindromic Repeats/Cas12a/13a System, Analytical Chemistry, February 2020, 92, 4029-4037), in view of Zhang (US 20210108267A1).
Regarding instant claim 1, Yuan teaches a method of detecting bacteria in a sample, comprising providing the sample (Page 4033, column 2, paragraph 3 to Page 4034, column 1, paragraph 1; Figure 4; Page 4031, column 1, paragraph 3; Figure 1); contacting the sample with i) a complex comprising a CRISPR nuclease having collateral nuclease activity and a crRNA comprising a nucleic acid sequence complementary to a nucleic acid sequence of a bacteria of interest (Page 4033, column 2, paragraph 3 to Page 4034, column 1, paragraph 1; Figure 4; Page 4031, column 1, paragraph 3; Figure 1); and ii) a first single stranded nucleic acid linker probe (Page 4033, column 2, paragraph 3 to Page 4034, column 1, paragraph 1; Figure 4; Page 4031, column 1, paragraph 3; Figure 1); incubating the sample with the complexes of parts i) and single stranded linker probes of parts ii) for a period of time (Page 4033, column 2, paragraph 3 to Page 4034, column 1, paragraph 1; Figure 4; Page 4031, column 1, paragraph 3; Figure 1); wherein when the nucleic acid sequence of the bacteria of interest is present in the sample, the collateral nuclease activity of the complex of part i) is activated and the first single stranded nucleic acid linker probe of part ii) is cleaved by the nuclease (Page 4033, column 2, paragraph 3 to Page 4034, column 1, paragraph 1; Figure 4; Page 4031, column 1, paragraph 3; Figure 1); wherein when the nucleic acid sequence of the bacteria of interest is not present in the sample, the collateral nuclease activity of the complex of part i) is not activated and the first single stranded nucleic acid linker probe of part ii) is not cleaved (Page 4033, column 2, paragraph 3 to Page 4034, column 1, paragraph 1; Figure 4; Page 4031, column 1, paragraph 3; Figure 1); contacting the sample with a first single stranded nucleic acid that hybridizes to a first nucleic acid sequence of the first single stranded nucleic acid linker probe of part ii) and a second single stranded nucleic acid that hybridizes to a second nucleic acid sequence of the first single stranded nucleic acid linker probe of part ii) (Page 4033, column 2, paragraph 3 to Page 4034, column 1, paragraph 1; Figure 4; Page 4031, column 1, paragraph 3; Figure 1); wherein the first and second single stranded nucleic acids hybridize to the first single stranded nucleic acid linker probe of part ii) when the first single stranded nucleic acid linker probe of part ii) is not cleaved, to form a complex comprising the first single stranded nucleic acid linker probe of part ii) and the first and second single stranded nucleic acids (Page 4033, column 2, paragraph 3 to Page 4034, column 1, paragraph 1; Figure 4; Page 4031, column 1, paragraph 3; Figure 1); detecting the presence or absence of the complex comprising the first single stranded nucleic acid linker probe of part ii) hybridized to the first and second single stranded nucleic acids, thereby detecting the presence or absence of nucleic acid from the bacteria of interest in the sample (Page 4033, column 2, paragraph 3 to Page 4034, column 1, paragraph 1; Figure 4; Page 4031, column 1, paragraph 3; Figure 1). Yuan teaches the detection system can be either a Cas12a system or a Cas13a system (Page 4031, column 1, paragraphs 3-4; Figure 1). Yuan teaches that these systems use different linker nucleic acids: ssDNA for Cas12a (Page 4031, column 1, paragraphs 3; Figure 1) and ssRNA for Cas13a (Page 4031, column 1, paragraphs 4; Figure 1). Yuan teaches that Cas13a may also be used to detect bacteria (Page 4034, column 2, paragraph 2 to Page 4035, column 1, paragraph 1; Figure 6). Yuan teaches that samples may come from actual subjects, obviating this variation (Page 4033, column 1, paragraph 2).
Yuan does not teach using two CRISPR complexes, two linker nucleic acids, and the related single stranded nucleic acids like those described above in multiplex to detect Chlamydia trachomatis and Neisseria gonorrhoeae.
Zhang, in a reasonably pertinent field, teaches that two CRISPR systems comprising Cas12a and Cas13a may be used in multiplex to detect multiple targets of interest, given the different trans-cleavage targets of Cas12 (ssDNA) and Cas13 (ssRNA) (Page 1, paragraphs [0006]-[0007]). Zhang teaches that these targets may be Chlamydia trachomatis and Neisseria gonorrhoeae (Pages 47-48, paragraph [0484]). Zhang teaches that the method may be performed on samples from human subjects (Abstract; Page 56, paragraph [0476]).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Yuan with the multiplex system of Zhang . Since Zhang teaches on CRISPR systems for multiplex detection of multiple targets of interest, which is reasonably pertinent to the CRISPR method of Yuan, one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because multiplex systems are useful in scenarios for human health, including bacterial strain typing (Zhang, Page 15, paragraph [0190]).
Regarding instant claim 2, Yuan, in view of Zhang, teaches the method of claim 1. As noted above, Zhang teaches that targets of interest may be Chlamydia trachomatis and Neisseria gonorrhoeae (Pages 57-58, paragraph [0484]). Zhang further teaches wherein the sample has been treated with an agent to release the nucleic acids from a cell for analysis of the materials within, wherein the agent lyses the cells (Page 41, paragraph [0356]). Given these teachings, it would be obvious that cells of or containing Chlamydia trachomatis and Neisseria gonorrhoeae could be lysed as this would amount to simple substitution of one known element for another to obtain predictable results (see MPEP 2141(III)).
Regarding instant claim 11, Yuan, in view of Zhang, teaches the method of claim 1. Yuan further teaches wherein the CRISPR nuclease comprises a Cas12a nuclease (Page 4031, column 1, paragraphs 3; Figure 1).
Regarding instant claim 18, Yuan, in view of Zhang, teaches the method of claim 1. Yuan further teaches wherein the first, second, third and/or fourth single stranded nucleic acids are bound to one or more labels, wherein the label is a nanoparticle (Figure 1).
Regarding instant claim 21, Yuan, in view of Zhang, teaches the method of claim 1. Yuan further teaches wherein the first single stranded nucleic acid is bound to a gold nanoparticle and the second single stranded nucleic acid is bound to a gold nanoparticle, wherein the third single stranded nucleic acid is bound to a gold nanoparticle and the fourth single stranded nucleic acid is bound to a gold nanoparticle (Figure 1).
Regarding instant claim 23, Yuan, in view of Zhang, teaches the method of claim 20. Yuan further teaches wherein a single gold nanoparticle is bound to multiple single stranded nucleic acids (Figure 1).
Regarding instant claim 24, Yuan, in view of Zhang, teaches the method of claim 1. Yuan further teaches wherein the complex comprising the single stranded nucleic acid linker probes of parts ii) and/or iv) hybridized to the single stranded nucleic acids form agglomerates, wherein a sample comprising the agglomerates has a different absorbance measurement than a sample that lacks agglomerates (Page 4029, column 1 to column 2; Figure 1a).
Regarding instant claim 27, Yuan, in view of Zhang, teaches the method of claim 18. Zhang further teaches wherein FAM and biotin may be used as detection molecules for a multiplex CRISPR system (Page 47, paragraph [0396]). Given these teachings, it would be obvious that FAM and biotin can be used as labels on the single stranded nucleic acids. One of ordinary skill in the art would have been motivated to make this modification because it amounts to simple substitution of one known element for another to obtain predictable results (see MPEP 2141(III)). FAM and biotin are also molecules that can be used in CRISPR detection systems, much like the gold nanoparticles taught by Yuan. Furthermore, the options laid out above for which single stranded nucleic acid each of FAM and biotin are bound to amount to simple substitution of one known element for another.
Regarding instant claim 29, Yuan, in view of Zhang, teaches the method of claim 1. Zhang further teaches loading of CRISPR detection systems onto a lateral flow assay to detect the presence or absence of a target of interest (Page 47, paragraph [0396]). Given these teachings, it would be obvious that the sample could be used on a lateral flow assay for detection. One of ordinary skill in the art would have been motivated to make this modification because it allows for production of a detectable signal in the presence of a target (Zhang, Page 47, paragraph [0396]).
Regarding instant claim 31, Yuan, in view of Zhang, teaches the method of claim 29. Zhang further teaches wherein the lateral flow assay comprises a biotin ligand in a test strip (Page 47, paragraph [0396]). Zhang also teaches that streptavidin is a binding partner of biotin (Page 46, paragraph [0391]).
Regarding instant claim 32, Yuan, in view of Zhang, teaches the method of claim 18. Zhang, as indicated for claim 27, teaches wherein the detectable molecules can comprise FAM and biotin. Zhang further teaches wherein an antibody is added to the sample that binds one or more labels on the single stranded nucleic acid, wherein the antibody is conjugated to a detectable label (Page 47, paragraph [0396]: gold nanoparticle modified with an anti-FITC antibody).
Regarding instant claim 39, Yuan teaches a method of detecting bacteria in a sample, comprising providing the sample (Page 4033, column 2, paragraph 3 to Page 4034, column 1, paragraph 1; Figure 4; Page 4031, column 1, paragraph 3; Figure 1); contacting the sample with i) a complex comprising a CRISPR nuclease having collateral nuclease activity and a crRNA comprising a nucleic acid sequence complementary to a nucleic acid sequence of a bacteria of interest (Page 4033, column 2, paragraph 3 to Page 4034, column 1, paragraph 1; Figure 4; Page 4031, column 1, paragraph 3; Figure 1); and ii) a first single stranded nucleic acid linker probe (Page 4033, column 2, paragraph 3 to Page 4034, column 1, paragraph 1; Figure 4; Page 4031, column 1, paragraph 3; Figure 1); d. incubating the sample with the complexes of parts i) and single stranded linker probes of parts ii) for a period of time (Page 4033, column 2, paragraph 3 to Page 4034, column 1, paragraph 1; Figure 4; Page 4031, column 1, paragraph 3; Figure 1); wherein when the nucleic acid sequence of the bacteria of interest is present in the sample, the collateral nuclease activity of the complex of part i) is activated and the first single stranded nucleic acid linker probe of part ii) is cleaved by the nuclease (Page 4033, column 2, paragraph 3 to Page 4034, column 1, paragraph 1; Figure 4; Page 4031, column 1, paragraph 3; Figure 1); wherein when the nucleic acid sequence of the bacteria of interest is not present in the sample, the collateral nuclease activity of the complex of part i) is not activated and the first single stranded nucleic acid linker probe of part ii) is not cleaved (Page 4033, column 2, paragraph 3 to Page 4034, column 1, paragraph 1; Figure 4; Page 4031, column 1, paragraph 3; Figure 1); contacting the sample with a first single stranded nucleic acid that hybridizes to a first nucleic acid sequence of the first single stranded nucleic acid linker probe of part ii) and a second single stranded nucleic acid that hybridizes to a second nucleic acid sequence of the first single stranded nucleic acid linker probe of part ii) (Page 4033, column 2, paragraph 3 to Page 4034, column 1, paragraph 1; Figure 4; Page 4031, column 1, paragraph 3; Figure 1); wherein the first and second single stranded nucleic acids hybridize to the first single stranded nucleic acid linker probe of part ii) when the first single stranded nucleic acid linker probe of part ii) is not cleaved, to form a complex comprising the first single stranded nucleic acid linker probe of part ii) and the first and second single stranded nucleic acids (Page 4033, column 2, paragraph 3 to Page 4034, column 1, paragraph 1; Figure 4; Page 4031, column 1, paragraph 3; Figure 1); detecting the presence or absence of the complex comprising the first single stranded nucleic acid linker probe of part ii) hybridized to the first and second single stranded nucleic acids, thereby detecting the presence or absence of nucleic acid from the bacteria of interest in the sample (Page 4033, column 2, paragraph 3 to Page 4034, column 1, paragraph 1; Figure 4; Page 4031, column 1, paragraph 3; Figure 1). Yuan teaches the detection system can be either a Cas12a system or a Cas13a system (Page 4031, column 1, paragraphs 3-4; Figure 1). Yuan teaches that Cas13a may also be used to detect bacteria (Page 4034, column 2, paragraph 2 to Page 4035, column 1, paragraph 1; Figure 6). Yuan teaches that samples may come from actual subjects, obviating this variation (Page 4033, column 1, paragraph 2).
Yuan does not teach detecting Chlamydia trachomatis.
Zhang, in a reasonably pertinent field, teaches that detection of bacteria targets may be performed by CRISPR systems (Page 1, paragraph [0006]; Page 1, paragraph [0010]; Page 2, paragraph [0015]; Pages 47-48, paragraph [0484]), with one option for a target being Chlamydia trachomatis (Pages 47-48, paragraph [0484]).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Yuan with the multiplex system of Zhang. Since Zhang teaches on CRISPR systems for detection of targets of interest, which is reasonably pertinent to the CRISPR method of Yuan, one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because it amounts to simple substitution of one known element for another (see MPEP 2141(III)). Yuan teaches that bacteria may be detected with a CRISPR method, while Zhang teaches Chlamydia trachomatis can be detected with a CRISPR system.
Regarding instant claim 69, Yuan teaches a method of detecting bacteria in a sample, comprising providing the sample (Page 4033, column 2, paragraph 3 to Page 4034, column 1, paragraph 1; Figure 4; Page 4031, column 1, paragraph 3; Figure 1); contacting the sample with i) a complex comprising a CRISPR nuclease having collateral nuclease activity and a crRNA comprising a nucleic acid sequence complementary to a nucleic acid sequence of a bacteria of interest (Page 4033, column 2, paragraph 3 to Page 4034, column 1, paragraph 1; Figure 4; Page 4031, column 1, paragraph 3; Figure 1); and ii) a first single stranded nucleic acid linker probe (Page 4033, column 2, paragraph 3 to Page 4034, column 1, paragraph 1; Figure 4; Page 4031, column 1, paragraph 3; Figure 1); d. incubating the sample with the complexes of parts i) and single stranded linker probes of parts ii) for a period of time (Page 4033, column 2, paragraph 3 to Page 4034, column 1, paragraph 1; Figure 4; Page 4031, column 1, paragraph 3; Figure 1); wherein when the nucleic acid sequence of the bacteria of interest is present in the sample, the collateral nuclease activity of the complex of part i) is activated and the first single stranded nucleic acid linker probe of part ii) is cleaved by the nuclease (Page 4033, column 2, paragraph 3 to Page 4034, column 1, paragraph 1; Figure 4; Page 4031, column 1, paragraph 3; Figure 1); wherein when the nucleic acid sequence of the bacteria of interest is not present in the sample, the collateral nuclease activity of the complex of part i) is not activated and the first single stranded nucleic acid linker probe of part ii) is not cleaved (Page 4033, column 2, paragraph 3 to Page 4034, column 1, paragraph 1; Figure 4; Page 4031, column 1, paragraph 3; Figure 1); contacting the sample with a first single stranded nucleic acid that hybridizes to a first nucleic acid sequence of the first single stranded nucleic acid linker probe of part ii) and a second single stranded nucleic acid that hybridizes to a second nucleic acid sequence of the first single stranded nucleic acid linker probe of part ii) (Page 4033, column 2, paragraph 3 to Page 4034, column 1, paragraph 1; Figure 4; Page 4031, column 1, paragraph 3; Figure 1); wherein the first and second single stranded nucleic acids hybridize to the first single stranded nucleic acid linker probe of part ii) when the first single stranded nucleic acid linker probe of part ii) is not cleaved, to form a complex comprising the first single stranded nucleic acid linker probe of part ii) and the first and second single stranded nucleic acids (Page 4033, column 2, paragraph 3 to Page 4034, column 1, paragraph 1; Figure 4; Page 4031, column 1, paragraph 3; Figure 1); detecting the presence or absence of the complex comprising the first single stranded nucleic acid linker probe of part ii) hybridized to the first and second single stranded nucleic acids, thereby detecting the presence or absence of nucleic acid from the bacteria of interest in the sample (Page 4033, column 2, paragraph 3 to Page 4034, column 1, paragraph 1; Figure 4; Page 4031, column 1, paragraph 3; Figure 1). Yuan teaches the detection system can be either a Cas12a system or a Cas13a system (Page 4031, column 1, paragraphs 3-4; Figure 1). Yuan teaches that Cas13a may also be used to detect bacteria (Page 4034, column 2, paragraph 2 to Page 4035, column 1, paragraph 1; Figure 6). Yuan teaches that samples may come from actual subjects, obviating this variation (Page 4033, column 1, paragraph 2).
Yuan does not teach detecting Neisseria gonorrhoeae.
Zhang, in a reasonably pertinent field, teaches that detection of bacteria targets may be performed by CRISPR systems (Page 1, paragraph [0006]; Page 1, paragraph [0010]; Page 2, paragraph [0015]; Pages 47-48, paragraph [0484]), with one option for a target being Neisseria gonorrhoeae (Pages 47-48, paragraph [0484]).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Yuan with the multiplex system of Zhang. Since Zhang teaches on CRISPR systems for detection of targets of interest, which is reasonably pertinent to the CRISPR method of Yuan, one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because it amounts to simple substitution of one known element for another (see MPEP 2141(III)). Yuan teaches that bacteria may be detected with a CRISPR method, while Zhang teaches Neisseria gonorrhoeae can be detected with a CRISPR system.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Yuan (Universal and Naked-Eye Gene Detection Platform Based on the Clustered Regularly Interspaced Short Palindromic Repeats/Cas12a/13a System, Analytical Chemistry, February 2020, 92, 4029-4037) and Zhang (US 20210108267A1), as applied to claims 1-2, 11, 18, 21, 23-24, 27, 29, 31-32, 39, and 69 above, and further in view of Ferreira (Assessment of the load and transcriptional dynamics of Chlamydia trachomatis plasmid according to strains’ tissue tropism, Microbiological Research, July 2013, 168, 333-339) and Lynn (Genetic Typing of the Porin Protein of Neisseria gonorrhoeae from Clinical Noncultured Samples for Strain Characterization and Identification of Mixed Gonococcal Infections, January 2005, 43, 368-375).
Regarding instant claim 5, Yuan, in view of Zhang, teaches the method of claim 1. Yuan further teaches wherein the crRNA is complementary to a nucleic acid sequence of a target gene (Page 4031, column 1, paragraphs 3-4; specific examples of crRNA complementary to targets in Figures 3, 4, and 5).
Yuan does not teach wherein the target gene of Chlamydia trachomatis is cryptic plasmid ORF6 segment sequence and the target gene of Neisseria gonorrhoeae is a major outer membrane protein porB.
Ferreira, in a reasonably pertinent field, teaches on assessment of pgp4 (e.g. cryptic plasmid ORF6, see page 41 of the instant specification) from Chlamydia trachomatis using qRT-PCR expression analysis (Page 335, column 1, paragraph 2; Page 335, column 2, paragraph 4), necessarily teaching it can be used as a target to detect Chlamydia trachomatis infections.
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method Yuan, in view of Zhang, with the target gene of Ferreira. Since Ferreira teaches on characterization of pgp4 as it relates to Chlamydia trachomatis, which is reasonably pertinent to the detection method of Yuan, in view of Zhang, one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because pgp4 has the highest mean expression value out of all ORFs on the cryptic plasmid (Ferreira, Page 335, column 2, paragraph 4).
Lynn, in a reasonably pertinent field, teaches that porB can be detected with other nucleic acid based testing for the detection and characterization of gonococcal infections resulting from Neisseria species, including Neisseria gonorrhoeae (Page 368, column 2, paragraph 2 to Page 369, column 1, paragraph 2), necessarily teaching it can be used as a target to detect Neisseria gonorrhoeae infections.
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method Yuan, in view of Zhang, with the target gene of Lynn. Since Lynn teaches on detection and characterization of porB as it relates to Neisseria gonorrhoeae infection, which is reasonably pertinent to the detection method of Yuan, in view of Zhang, one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because the porin protein is important to pathogenicity of the organism (Lynn, Page 368, column 2, paragraph 2 to Page 369, column 1, paragraph 1), and therefore would necessarily be available as a target to detect infection.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Yuan (Universal and Naked-Eye Gene Detection Platform Based on the Clustered Regularly Interspaced Short Palindromic Repeats/Cas12a/13a System, Analytical Chemistry, February 2020, 92, 4029-4037) and Zhang (US 20210108267 A1), as applied to claims 1-2, 11, 18, 21, 23-24, 27, 29, 31-32, 39, and 69 above, and further in view of GenBank I (GenBank accession number NZ_CP041585.1 [online]. GenBank, [2021] [retrieved on February 5th, 2026]. Retrieved from: https://www.ncbi.nlm.nih.gov/nuccore/1712917863?sat=51&satkey=28209889) and GenBank II (GenBank accession number CP042654.1 [online]. GenBank, [2021] [retrieved on February 5th, 2026]. Retrieved from: https://www.ncbi.nlm.nih.gov/nuccore/CP042654.1).
Regarding instant claim 6, Yuan, in view of Zhang, teaches the method of claim 1. Zhang further teaches on similar structures to Yuan’s linkers, called bridge molecules (Page 38, paragraph [0337]). These bridge molecules are intended to hold gold nanoparticles in aggregate if left uncleaved (Page 38, paragraph [0337]). Zhang further teaches that at least a portion these bridge molecules comprise RNA or DNA (Page 38, paragraph [0337]). Given these teachings, one of ordinary skill in the art could reasonably use any RNA or DNA sequence as a linker or bridge molecule, including a nucleic acid sequence of the target gene of Chlamydia trachomatis for the first single stranded linker probe and a nucleic acid sequence of the target gene of Neisseria gonorrhoeae for the second single stranded linker probe, given that the nucleic acid sequence of the target gene is known. As taught by GenBank I, the full genome of strains of Neisseria gonorrhoeae are known (whole document). As taught by GenBank II, the full genome of strains of Chlamydia trachomatis are known (whole document).One of ordinary skill in the art would have been motivated to do so because it amounts to simple substitution of one known element for another to obtain predictable results (see MPEP 2141(III)).
Claims 36 and 37 are rejected under 35 U.S.C. 103 as being unpatentable over Yuan (Universal and Naked-Eye Gene Detection Platform Based on the Clustered Regularly Interspaced Short Palindromic Repeats/Cas12a/13a System, Analytical Chemistry, February 2020, 92, 4029-4037) and Zhang (US 20210108267 A1), as applied to claims 1-2, 11, 18, 21, 23-24, 27, 29, 31-32, 39, and 69 above, and further in view of Crnogorac (US 20170044601 A1).
Regarding instant claim 36, Yuan, in view of Zhang, teaches the method of claim 1. Zhang has already been shown to teach that targets may be Chlamydia trachomatis and Neisseria gonorrhoeae (Pages 47-48, paragraph [0484]).
Neither reference teaches wherein the sample from the subject comprises a single sample, wherein detecting the presence or absence of nucleic acid from Chlamydia trachomatis and Neisseria gonorrhoeae is performed on a single sample.
Crnogorac, in a reasonably pertinent field, teaches on assays that evaluate multiple targets (Page 6, paragraph [0063]). Crnogorac also teaches a sample from which target polynucleotides are derived can comprise a plurality of polynucleotides from a single individual (Pages 8-9, paragraph [0079]). Crnogorac further teaches that samples comprise a multitude of different DNA options, including a mixture of bacterial populations (Page 8, paragraph [0078]).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Yuan, in view of Zhang, with the sample arrangement of Crnogorac, where detecting the presence or absence of nucleic acid from Chlamydia trachomatis and Neisseria gonorrhoeae is performed on a single sample. Since Crnogorac teaches on assays that include looking at bacteria, which is reasonably pertinent to the method of Yuan, in view of Zhang, one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because Crnogorac offers point-of-care applications and field detection of pathogens (Pages 1-2, paragraph [0010]).
Regarding instant claim 37, Yuan, in view of Zhang, teaches the method of claim 1. Zhang has already been shown to teach that targets may be Chlamydia trachomatis and Neisseria gonorrhoeae (Pages 47-48, paragraph [0484]).
Neither reference teaches wherein the sample from the subject comprises a first sample for detecting the presence or absence of nucleic acid from Chlamydia trachomatis and a second sample for detecting the presence or absence of nucleic acid from Neisseria gonorrhoeae.
Crnogorac, in a reasonably pertinent field, teaches on assays that evaluate multiple targets (Page 6, paragraph [0063]). Crnogorac also teaches a sample from which target polynucleotides are derived can comprise multiple samples from the same individual (Pages 8-9, paragraph [0079]). Crnogorac further teaches that samples comprise a multitude of different DNA options, including bacterial populations (Page 8, paragraph [0078]).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Yuan, in view of Zhang, with the sample arrangement of Crnogorac, where the sample from the subject comprises a first sample for detecting the presence or absence of nucleic acid from Chlamydia trachomatis and a second sample for detecting the presence or absence of nucleic acid from Neisseria gonorrhoeae. Since Crnogorac teaches on assays that include looking at bacteria, which is reasonably pertinent to the method of Yuan, in view of Zhang, one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because Crnogorac offers point-of-care applications and field detection of pathogens (Pages 1-2, paragraph [0010]).
Claim 100 is rejected under 35 U.S.C. 103 as being unpatentable over Yuan (Universal and Naked-Eye Gene Detection Platform Based on the Clustered Regularly Interspaced Short Palindromic Repeats/Cas12a/13a System, Analytical Chemistry, February 2020, 92, 4029-4037) and Zhang (US 20210108267A1), as applied to claims 1-2, 11, 18, 21, 23-24, 27, 29, 31-32, 36-37, 39, and 69 above, and further in view of Yonke (Chlamydial and Gonococcal Infections: Screening, Diagnosis, and Treatment, American Family Physician, April 2022, 105, 388-396).
Regarding instant claim 100, Yuan, in view of Zhang, teaches the method of claim 1.
Neither reference teaches the method further comprising administering to the subject an effective amount of one or more agents to treat an infection caused by Chlamydia trachomatis and/or Neisseria gonorrhoeae.
Yonke, in a reasonably pertinent field, teaches on treating an infection caused by Chlamydia trachomatis and/or Neisseria gonorrhoeae (Page 392, column 2, paragraph 3) after detection with nucleic acid amplification techniques (Page 391, column 2, paragraph 2 to Page 392, column 1, paragraph 1).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Yuan, in view of Zhang, with the treatment of Yonke. Since teaches on current guidelines for treatment of chlamydia and gonorrhea, which is reasonably pertinent to detecting a Chlamydia trachomatis and/or Neisseria gonorrhoeae infection as taught by Yuan, in view of Zhang, one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because untreated infections can lead to other issues like pelvic inflammatory disease and easier transmission of HIV (Yonke, Page 388, column 1).
Conclusion
All claims are rejected.
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/ALLISON E SCHLOOP/Examiner, Art Unit 1683
/Robert T. Crow/Primary Examiner, Art Unit 1683