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 .
Status of the Application
1. Claims 1-2 and 4-9 are pending and subject to examination on the merits. Claim 2 is withdrawn from consideration as being drawn to non-elected subject matter. Claims 1 and 4-9 are currently under examination.
Priority
2. Acknowledgment is made for the Applicant’s claim for domestic priority based on the US provisional application PRO 62/930,147 filed 04 November 2019.
Withdrawn Objections/Rejections
3. The objection to the specification for the presence of a hyperlink is withdrawn, since the specification was edited to delete the hyperlink.
4. The objection to claim 3 for the utilization of “BV” without a first definition is withdrawn, since the claim was cancelled and amended claim 1 defines the abbreviation before use.
5. The 35 U.S.C. 103 rejection of claims 1 over Gilbert et al., Anderson et al., and Amegashie et al. is withdrawn due to claim amendments and replaced with the modified rejection found below.
6. The 35 U.S.C. 103 rejection of claims 3-5 over Gilbert et al., Anderson et al., and Amegashie et al. in further view of Akins and Sobel is withdrawn, since claim 3 was cancelled and claims 4 and 5 are now dependent on claim 1.
New and Maintained/Modified Rejections—due to claim amendments
Claim Rejections - 35 USC § 101
7. 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.
8. Claims 1 and 4-9 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a natural phenomenon) without additional elements that integrate the judicial exception into a practical application. An analysis with respect to the claims as a whole reveals that they do not include additional elements that integrate the judicial exception into a practical application. See MPEP 2106.
Analysis of subject-matter eligibility under 35 U.S.C. § 101 requires consideration of the following steps:
Step (1) whether the claim is directed to one of the four categories recited in §101 (process, machine, manufacture or composition of matter);
Step (Revised 2A - Prong 1) do the claims recite an abstract idea (mathematical concepts, mental processes or method of organizing human activity), law of nature or natural phenomenon;
Step (Revised 2A - Prong 2) do the claims recite additional elements that integrate the judicial exception into a practical application; and
Step (2B) whether the claim as a whole recites something that amounts to significantly more than the judicial exception. (See 2019 Revised Patent Subject Matter Eligibility Guidance (2019 PEG)).
Step 1: Yes; the claims are directed to a process.
Step 2A – Prong 1: Yes, the claims recite a natural correlation of the process and/or mental process of quantifying shed epithelial cells as a diagnostic feature of bacterial vaginosis and subsequently treating the infection (claim 1) in both asymptomatic (claim 4) and symptomatic individuals (claim 5), where treatment is selected from the conventional treatment, specifically, the application of a probiotic bacteria, Lactobacillus casei (claims 6-8) or an antimicrobial consisting of boric acid (claims 6 and 9).
Step 2A – Prong 2: No, the claims do not recite any additional elements that integrate the judicial exception into a practical application because the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because there is no other meaningful limitations not already present when the elements are considered separately; i.e. they are solely directed to a naturally occurring correlation of cell counts that inform of stages of bacterial vaginosis, wherein the correlation is identified by a mental process (e.g. abstract idea), and then for claims 4-9, merely conventional methods and conventional treatments (See MPEP 2106.04(a)(2)(III) and all of 2106.04 and 2106.05).
Step 2B: As noted in answering that of 2A – This judicial exception is not integrated into a practical application because the additional elements considered together or separately are conventional methods well-known in the art. Obtaining vaginal secretions and doing epithelial cell counts is routine to the art and merely identifying the natural correlation that exists in nature between the amount of total cell shed counts, superficial cells counts and parabasal cell counts does not transform what already exists in nature for these cells. Furthermore, for claims 4-9, treating by any or all conventional means known in the art as such a level of generality (e.g. essentially telling those to “apply it” for the exception – See MPEP 2106.05(f) and 2106.04(d)), does not transform these method claims either.
As such, the claims do not amount to more than a known a naturally occurring correlation between kinds of cells and their counts and the states, and essentially of a mental process of identifying said correlation of said bacterial vaginosis and a subsequent generic method to treat said bacterial vaginosis by well-known and conventional methods, i.e. the application of a antibiotics, probiotics/prebiotics and/or boric acid (See Verstraelen and Verhelst, abstract; p. 10, paragraph 2; p. 8, 2nd column).
Claim Rejections - 35 USC § 103
9. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
10. 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.
11. Claims 1 and 4-5 are rejected under 35 U.S.C. 103 as being unpatentable over Gilbert et al. (Gilbert et al., 2013, PLOS ONE—cited on the Information Disclosure Statement dated 10 August 2022), Anderson et al (Anderson et al., 2014, Am J Reprod Immunol--cited on the Information Disclosure Statement dated 15 November 2023), and Amegashie et al (Amegashie et al., 2017, PLOS ONE—cited on the Information Disclosure Statement dated 15 November 2023), and Akins and Sobel (Akins and Sobel, 2019, US2019/0264263 A1—cited on the information disclosure statement dated 10 August 2022). Regarding claim 1, drawn to a method of diagnosing the stage of bacterial vaginosis by obtaining a sample of vaginal secretion from the subject, determining the total number of shed epithelial cells, and determining the maturity of said shed epithelial cells for superficial cells and parabasal cells in the sample to diagnose Stage I or Stage II of bacterial vaginosis, wherein Stage I is diagnosed with the total cell shedding log10 cell count is from about 2.4- about 3.0, superficial cells log10 cell count from about 1.5- about 2.7, and parabasal cells log 10 cell count is from about 1.1 to about 2.5, and wherein Stage II bacterial vaginosis is diagnosed when total cell shedding log10 cell count is from about 1.5- about 2.5, superficial cells log10 cell count is about 1.0- about 1.7, and parabasal cells log10 cell count is about 1.2- about 2.3, and treating Stage II BV whether symptomatic or asymptomatic, Gilbert et al. teaches a method of diagnosing the stage of bacterial vaginosis in a subject by utilizing a murine model with a clinical isolate of Gardnerella vaginalis (Abstract; lines 2-5). Gilbert continues to a measurable epithelial exfoliation in clinical samples from women with bacterial vaginosis (BV) response compared to women with normal flora (Abstract; lines 11-12). Specifically, Gilbert et al. teach obtaining a sample from vaginal secretion from the subject via vaginal swabs as part of the contraceptive CHOICE project. Gilbert et al. then teach gram staining and analyzing for epithelial exfoliation by enumerating epithelial cells in samples from bacterial vaginosis positive and negative patients, where there is an increase in the total epithelial cells per field in BV+ vs. BV- samples (p. 11, column 2, Clinical Specimen Handling and Analysis of epithelial Exfoliation; Fig. 7). Gilbert et al. teaches that the increase of shed epithelial cells was positively correlated with the CFU (BV) found in the sample (Fig. 6C; p. 4, column 2, paragraph 2). Therefore, increased CFU led to an increase in shed epithelial cells.
Gilbert et al. does not teach the determination of the total number of shed cells in log10 count and the maturity of the epithelial cells as superficial and parabasal. Anderson et al. teaches that the vaginal epithelium undergoes differentiation and contains several distinct layers or “strata,” including the basal layer, the superbasal layer, and a superficial layer (p. 618 last line- p. 619 line 5), where the superficial cells consist of keratinized enucleated, dead, and flattened cells (p. 619; lines 10-12) and the parabasal cells consist of mitotically active cells (p. 619, line 10) (See Fig. 1B). Anderson et al. continues to teach that exfoliation of the cell layers is an effective way to eliminate pathogens that have attached to the vaginal surface or that bind to sloughed ‘decoy’ cells (p. 619, last paragraph-p. 621, first paragraph).
Gilbert et al. and Anderson et al. do not specifically teach Stage I and Stage II BV. Amegashie et al. teaches BV-, BVint, and BV+ cohorts, corresponding to Nugent scores, where BV- is Nugent 0-3, BVint is Nugent 4-6, and BV+ is Nugent 7-10) (p. 3, second paragraph). Amegashie et al. continue to teach that the previous study (Gilbert et al.) did not test the epithelial exfoliation among all three groupings of Nugent scores, i.e. the inclusion of BVint (p. 2, last paragraph). Amegashie et al. continues to teach an increase in epithelial exfoliation in both BVint and BV+ samples (Fig. 1).
Regarding the cell numbers recited in the claim, Amegashie et al. demonstrates counting epithelial cells in the microscope fields and an increase in epithelial cells shed in BVint and BV+ samples (Fig. 1). Utilizing a known dilution factor and total fluid volume, it would be routine to a person of ordinary skill in the art, to obtain cell counts of total epithelial cells. Obtaining the ranges recited in the claim would therefore be routine optimization.
Routine optimization to determine the optimal working conditions of an invention is not non-obvious. The MPEP states, "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP Section 2144.05.
The teachings of Gilbert et al., Anderson et al., and Amegashie et al. do not teach a method of treating bacterial vaginosis based on the results of the diagnostic method. Regarding claims 1 and 4-5, drawn to treating the subject for bacterial vaginosis if the subject is diagnosed with asymptomatic (claims 1 and 4) Stage I BV and treating the subject if the subject is diagnosed with symptomatic (claims 1 and 5) Stage II BV, Akins and Sobel teach a method of identifying and treating individuals for BV recurrence that are asymptomatic by obtaining a vaginal sample after a course of treatment for BV, amplifying the bacterial DNA present, determining the cycle (Cq) score for unblocked samples and subtracting the Cq of the blocked samples, and predicting recurrence of BV in the subject if the ΔCq is below 3 and symptomatic or asymptomatic, where that subject is then treated and treatment assessed for effectiveness (claim 20, paragraphs 0084, 0116-0117).
Therefore, it 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 combine the teachings of Gilbert et al., Anderson et al., and Amegashie et al. with Akins and Sobel to devise a method of identifying symptomatic and asymptomatic BV patients by enumerating exfoliated epithelial cells and subsequently treating said patients to assess the health of a microbiome and further categorize non-dominant species populations in samples as taught by Amegashie et al (paragraph 0034). One would be motivated to combine these teachings to arrive at the instant claims to mitigate the risks from BV, such as increased susceptibility to HIV, infections following surgical procedures, such as hysterectomies or abortions, complications from pregnancy, and susceptibility to other STDs, such as herpes simplex virus, chlamydia, and gonorrhea. There would be a reasonable expectation of success, yielding no surprising results when combining the teachings of Gilbert et al., Anderson et al., and Amegashie et al. with Akins and Sobel, since Akins and Sobel describe treating symptomatic and asymptomatic BV patients.
12. Claims 6-9 are rejected under 35 U.S.C. 103 as being unpatentable over Gilbert et al. (Gilbert et al., 2013, PLOS ONE—cited on the Information Disclosure Statement dated 10 August 2022), Anderson et al (Anderson et al., 2014, Am J Reprod Immunol--cited on the Information Disclosure Statement dated 15 November 2023), Amegashie et al (Amegashie et al., 2017, PLOS ONE—cited on the Information Disclosure Statement dated 15 November 2023), and Akins and Sobel (Akins and Sobel, 2019, US2019/0264263 A1—cited on the information disclosure statement dated 10 August 2022) as applied to claims 1 and 4-5 above, and further in view of Verstraelen and Verhelst (Verstraelen and Verhelst, 2009, Expert Rev. Anti Infect. Ther—cited herein).
The teachings of Gilbert et al, Anderson et al., Amegashe et al., and Akins and Sobel are discussed above and incorporated into the instant rejection.
Gilbert et al., Anderson et al., Amegashe et al., and Akins and Sobel do not teach the treatment of BV with probiotics, such as L. casei (claims 6-8), or boric acid (claim 6 and 9). Verstraelen and Verhelst teach that bacterial vaginosis can be treated with alternative treatments, such as vaginal acidifying and buffering agents and probiotics for long term prevention (abstract). Specifically, Verstraelen and Verhelst teach alternative or adjuvant treatment with probiotics, such as Lactobacillus sp. and Bifidobacterium sp., including Lactobacillus casei (p. 8, column 2). Additionally, Verstraelen and Verhelst teach the utilization of boric acid in treating recurrent BV (p. 10, paragraph 2).
Therefore, it 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 combine the teachings of Gilbert et al, Anderson et al., Amegashe et al., and Akins and Sobel with that of Verstraelen and Verhelst to treat BV with probiotics or boric acid because they serve as an adjuvant to standard treatments with antibiotics and hold promise for long-term prevention as taught by Verstraelen and Verhelst (abstract). One would be motivated to combine these teachings to arrive at the instant claims to reduce infection with secondary agents, such as T. vaginalis, N. gonorrhoeae, C. trachomatis, HSV-2, and HIV-1, as taught by Verstraelen and Verhelst (p. 1, bottom of first column). Therefore, it 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 combine the teachings of Gilbert et al, Anderson et al., Amegashe et al., and Akins and Sobel with that of Verstraelen and Verhelst to treat BV with probiotics or boric acid, since Verstraelen and Verhelst teach probiotic and boric acid treatment of recurrent BV.
Applicant’s Arguments and Examiner’s Rebuttal:
The applicant traverses the 35 U.S.C. 101 rejection of claims 1 and 3-5 for being directed to a nonpatentable subject matter. The applicant traverses the 35 U.S.C. 103 obviousness rejection of claim 1 over Gilbert et al., Anderson et al., and Amegashie et al. due to the utilization of Nugent scoring (discussed below), and further, the applicant traverses the 35 U.S.C. 103 obviousness rejection of claims 3-5 over Gilbert et al., Anderson et al., and Amegashie et al., in further view of Akins and Sobel, since claim 3 was cancelled and the dependency of 4-5 was changed to claim 1.
First, the applicant argues that the action of treating Stage II BV (asymptomatic) is not a natural phenomenon, and further, the addition of this treatment confines the claim to a useful application. The examiner respectfully disagrees. The claims are drawn to a natural phenomenon present in women, i.e. the shedding of epithelial cells. Additionally, the correlation of cell numbers to disease state is identified by a mental process (e.g. abstract idea). The treatment thereof, claims 4-9, are merely conventional methods and conventional treatments (See MPEP 2106.04(a)(2)(III) and all of 2106.04 and 2106.05). These treatments are well-known in the literature (See Verstraelen and Verhelst as discussed above).
Second, regarding the 35 U.S.C. 103 rejection, the applicant argues that Gilbert et al. does not teach a method to diagnose BV and/or the stages of BV by enumerating epithelial cells. The examiner agrees insofar that Gilbert et al. was not relied upon to anticipate the current method; therefore, Gilbert et al. does not teach all aspects of the current invention. Gilbert et al. does teach enumeration of epithelial cells and demonstrates a positive correlation between uninfected and infected individuals (as presented above).
Third, the applicant argues that Anderson et al. does not teach BV or a way to diagnose BV. The examiner agrees insofar that the Anderson et al. reference was not utilized to anticipate the instant claims. The Anderson et al. reference was introduced to teach the cell layers present in the vaginal tissue and the natural phenomenon that is cellular exfoliation, especially when exposed to a pathogen.
Fourth, the applicant argues that Amegashe et al. did not distinguish between the Stage I and Stage II BV with the epithelial cell counts. The examiner agrees insofar that Amagashe et al. did not recite the ranges of the instant claim or set out to determine these recited ranges; however, as described above, the recited ranges are considered optimization to the examiner. These ranges could be and would be determined by routine optimization through cell counting by a skilled artisan.
Fifth, the applicant argues that a skilled artisan would not be motivated nor they have a reasonable chance of success to correlate bacterial counts and epithelial cell counts to guess whether epithelial cell counts were even relevant to BV diagnosis or to come up with the precise claims presented. The examiner disagrees. Gilbert et al. and Amagahe et al. both determine a correlation between epithelial cell counts and BV. Although the instant claims recite specific ranges and define those ranges in an asymptomatic vs. symptomatic infection, a skilled artisan would still be able to a) correlate the epithelial shedding vs. bacterial infection, since Gilbert et al. and Amagashe et al. both demonstrated this previously, and b) optimize the cell counts, since this is a routine method utilized in the field, as demonstrated by all three references, Gilbert et al., Amagashe et al., and Anderson et al., where specifically, each are able to count shed cells and correlate said number to a disease state.
Sixth, the applicant argues that the second obviousness rejection is entirely moot, since claim 3 was deleted, and claims 4-5 now depend from claim 1. These claims and claim amendments are addressed in the above, new 35 U.S.C. 103 rejection of obviousness found above over Gilbert et al., Anderson et al., and Amegashie et al. with Akins and Sobel.
New claims 6-9 are addressed in the above new 35 U.S.C. 103 obviousness rejection over Gilbert et al., Anderson et al., and Amegashie et al. with Akins and Sobel and in further view of Verstraelen and Verhelst.
The examiner does not find the arguments presented by the applicant persuasive, and for these reasons, the rejections of record above apply.
Conclusion
13. All claims are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
14. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CIARA A MCKNIGHT whose telephone number is (703)756-4791. The examiner can normally be reached M-F 8:00am-4:30pm.
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/CIARA A MCKNIGHT/Examiner, Art Unit 1656
/SUZANNE M NOAKES/Primary Examiner, Art Unit 1656