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 .
DETAILED ACTION
Claims 1, 3-12, 14, and 16-17 are pending.
Response to Amendment
Applicant amended claim 1 to add new limitation “at risk of preterm birth”, the limitation “produce hydrogen peroxide”, the limitation “up to 34 weeks after her last menstrual period” and the limitation “antibiotic targeting vaginal bacteria” of now canceled claims 2, 13 and 15, respectively. Applicant amended claim 5 and limited the claim to “the subject is in the first or second trimester of pregnancy”.
The objection to the specification is withdrawn in view of the amendment.
The rejection of claim 5 under 35 U.S.C. 112(d) is withdrawn in view of the amendment.
Information Disclosure Statement
The information disclosure statement (IDS) filed on 01/30/2026 is acknowledged and has been considered.
Abstract
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The abstract of the disclosure is objected to because it is not within the range of 50 to 150 words in length and contains legal phraseology. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
New Rejections Necessitated by the amendment
Applicant amended claim 1 and limited the scope of the claim to require administration up to 34 weeks after subject’s last menstrual period, production of hydrogen peroxide and antibiotic targeting vaginal bacteria and limited the population to a pregnant female subject at risk of preterm birth.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 3-12, 14, and 16-17 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites comprising administering to the subject up to 34 weeks after her last menstrual period a composition comprising Lactobacillus crispatus cells. The claim is indefinite because it is not clear if the up to 34 weeks after her last menstrual period refers to the pregnancy stage of the subject or refers to the duration of administering the composition. It is not clear if the composition is administered for a duration of 34 weeks or less and if the composition is administered for an undefined time to a pregnant subject that it at most 34 weeks pregnant.
Claim 1 recites pregnant female subject at risk of preterm birth. The claim is indefinite because the metes and bounds of the limitation are not clear. It is not clear the criteria required to label a pregnant female at risk of preterm birth. While some medical conditions such as a history of a prior preterm birth, specific uterine anomalies, and bacterial vaginosis are considered high-risk indicators, any pregnancy can carry a baseline risk of preterm birth.
Claims 3-12, 14, and 16-17 which depend from claim 1 do not cure the indefiniteness and are also rejected.
Maintained Rejection
Claim Rejections - 35 USC § 112
Biological Deposit
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 3-12, 14, and 16-17 remain rejected under 35 U.S.C. 112, first paragraph, as containing subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The specification fails to provide an adequate written description of the invention and fails to provide an enabling disclosure, because the specification does not provide evidence that the claimed biological materials are: (1) known and readily available to the public; (2) reproducible from the written description; or, (3) deposited in compliance with the criteria set forth in 37 CFR 1.801-1.809. The specification lacks complete deposit information for the Lactobacillus crispatus cells. Because it is not clear that the deposited cells possessing the properties Lactobacillus crispatus cells of strains CTV-05, SJ-3C, MV-3A-US and MV-1A-US are known and publicly available or can be reproducibly isolated without undue experimentation, and because the invention of claims 1, 3-12, 14, and 16-17 claims or uses the Lactobacillus crispatus cells, a suitable deposit for patent purposes is required. Accordingly, filing of evidence of the reproducible production of the Lactobacillus crispatus cells is necessary to practice the instant invention or filing of evidence of deposit is required. Without a publicly available deposit of the above Lactobacillus crispatus cells, one of ordinary skill in the art could not be assured of the ability to practice the invention as claimed. Exact replication of the Lactobacillus crispatus cells is an unpredictable event. Applicants must comply with the criteria set forth in 37 CFR 1.801-1.809.
If the deposits are made under the terms of the Budapest Treaty, then an affidavit or declaration by Applicant, or a statement by an attorney of record over his or her signature and registration number, stating that the Lactobacillus crispatus cells have been deposited under the Budapest Treaty, that the Lactobacillus crispatus cells will be irrevocably and without restriction or condition released to the public upon the issuance of a patent and that the Lactobacillus crispatus cells will be replaced should they ever become non-viable, would satisfy the deposit requirement made herein.
If the deposits have not been made under the Budapest Treaty, then in order to certify that the deposits meet the criteria set forth in 37 CFR 1.801-1.809, applicant may provide assurance of compliance by an affidavit or declaration, or by a statement by an attorney of record over his or her signature and registration number.
For each deposit made pursuant to these regulations, the specification shall contain:
The accession number for the deposit;
The date of the deposit;
A description of the deposited biological material sufficient to specifically identify it and to permit examination; and
The name and address of the depository.
A viability statement for each deposit of a biological material not made under the Budapest Treaty on the International Recognition of the deposit of Microorganisms for the Purposes of Patent Procedure must be filed in the application and must contain:
The name and address of the depository;
The name and address of the depositor;
The date of deposit;
The identity of the deposit and the accession number given by the depository; (5) The date of the viability test;
The procedures used to obtain a sample if the test is not done by the depository; and
A statement that the deposit is capable of reproduction.
Applicant must assure that:
Access to the deposit will be available during pendency of the patent application making reference to the deposit.
All restrictions imposed by the depositor on the availability to the public of the deposited material will be irrevocably removed upon the granting of the patent.
In the instant application, at least the following issues exist. Searching for the accession numbers, strain name, or even species at ATCC.org does not result in any results for the strains SJ-3C or CTV-05 which is the claimed depository for these strains. Searching for strains MV-3A-US or MV-1A-US yields results at BEI resources however the accession numbers, and address are not listed in the specification, and the results are out of stock and have restrictions on availability.
If a deposit is made after the effective filing date of the application for patent in the United States, a verified statement is required from a person in a position to corroborate that the biological material described in the specification as filed is the same as that deposited in the depository, stating that the deposited material is identical to the biological material described in the specification and was in the Applicant’s possession at the time the application was filed.
As a possible means for completing the record, applicant may submit a copy of the contract with the depository for deposit and maintenance of each deposit along with the necessary statements in order to meet the criteria set forth in 37 CFR 1.801-1.809.
Applicant’s attention is directed to In re Lundak, 773 F.2nd. 1216, 227 USPQ 90 (CAFC 1985) and 37 CRF 1.801-1.809 for further information concerning deposit practice.
Written Description
Claims 1-181, 3-12, 14, and 16-17 remain rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus.
Nature of the Invention
The nature of the invention is a method of treatment wherein a composition containing Lactobacillus crispatus is administered to a pregnant female subject to increase the probability of full-term birth. The pregnant female subject is at risk of preterm birth and has not been pretreated with antibiotics.
Breadth of Strains
In the current office action, the examiner will refer to a genus as a plurality of options or embodiments. And this is not to be confused with a phylogenetic classification of the genus. If the examiner wishes to refer to a phylogenetic classification the examiner will write “phylogenetic genus” or “phylogenetic species” in order to provide clarity of the record. As an example, in this application the phylogenetic species of L. crispatus is treated as a genus of strains.
The claims of the instant application are drawn to a method of using a genus of L. crispatus strains to increase the probability of full-term birth in female subjects.
The claims encompass all members of the phylogenetic species that express specific genes and specifically claim 3 more strains, SJ-3C, MV-3A-US and MV-1A-US. The breadth of these claims could encompass thousands of strains.
The specification of the instant application details a clinical protocol wherein the inventors’ selected subjects for treatment with L. crispatus CTV-05 in a formulation labeled LACTIN-V for the prevention of preterm birth in pregnant subjects. This is the only strain which the applicants have written description for and represents only a single species of a genus of strains. There is no data or examples in the specification showing the effect of SJ-3C, MV-3A-US and MV-1A-US.
The following quote refers to phylogenetic species, Dhanasekar et al. (Prenatal Probiotics: The Way Forward in Prevention of Preterm Birth, Journal of Clinical Gynecology and Obstetrics, Vol. 8, No. 3, Sept 2019, of record in Office Correspondence mailed on 01/22/2026) teaches “The effect of Lactobacilli on the immune system and their vaginal colonization ability are species- and strain-specific. Among many strains of Lactobacilli, Lactobacillus rhamnosus GR1 and Lactobacillus reuteri RC14 are found to have excellent colonizing capability and are the preferred Lactobacilli strain for the treatment of urogenital tract infections. Whereas some strains like Lactobacillus rhamnosus GG and Lactobacillus acidophilus are not well suited to colonizing the vagina” on page 65. This teaches that within the art variation among strains of bacteria can result in very different outcomes, specifically one will note that the same phylogenetic species L. rhamnosus contains 2 strains with different colonization capabilities in the same phylogenetic genus as L. crispatus.
It is also well known in the art of bacteriology that genetic diversity is high and any two strains of bacteria may have different genes that change the properties and capabilities of the members of the phylogenetic species. In L. crispatus this is true as well as taught by Ojala et al. (Comparative genomics of Lactobacillus crispatus suggests novel mechanisms for the competitive exclusion of Gardnerella vaginalis, BMC Genomics 2014, of record in Office Correspondence mailed on 01/22/2026) “the current L. crispatus core genome to be comprised of 1,224 ortholog groups that were conserved across all the ten analyzed strains” on page 7 and further teaches “L. crispatus genomes comprised 3,929 ortholog groups” when discussing the pan genome on page 6. This leaves uncertainty in which strains will and will not be effective in preventing preterm birth because there are thousands of genes which may be different between any given strains and there is uncertainty as to which ones may be missing or altered in any given strain and affect the ability of L. crispatus to colonize, persist and affect the microbiome of the vagina and ultimately reduce preterm birth.
In addition, Del Barco et al. (The Effect of Probiotics on Preterm Birth Rates in Pregnant Women After a Threatened Preterm Birth Episode (The PROPEV Trial) Biomedicines 2025) teach a clinical trial in which Lactobacillus strains one of which was L. crispatus LBV88 (page 4) are vaginally administered to a cohort of pregnant females with a singleton gestation with a threatened preterm labor episode (page 3). Del Barco et al. teaches “a trend toward a lower rate of preterm birth < 34 weeks was noted in the placebo group (17.8% vs. 9.0%, p = 0.0844), and a statistically significant difference was observed for preterm birth < 32 weeks (12.2% vs. 3.3%, p = 0.0260)”. In this case even though L. crispatus was administered to a similar cohort, preterm birth was trending toward an increase in the treated group when L. crispatus LBV88 was used for treatment as opposed to the inventor’s use of L. crispatus CTV-05. Prior art Laue et al. ("Effect of a yoghurt drink containing Lactobacillus strains on bacterial vaginosis in women–a double-blind, randomised, controlled clinical pilot trial." Beneficial Microbes 9.1 (2018): 35-50) reports L. crispatus LBV88 has an acidification capacity, produces H2O2 and utilizes glycogen (Abstract). Applicant discloses that a functionally expressed pullulanase gene confers L. crispatus the ability to utilize glycogen (specification page 10). Prior art Veer et al. ("Comparative genomics of human Lactobacillus crispatus isolates reveal genes for glycosylation and glycogen degradation: implications for in vivo dominance of the vaginal microbiota." Microbiome 7.1 (2019): 49) reports that among 33 studied L. crispatus strains including strains isolated from vaginal samples with dysbiotic vaginal microbiota, all except two strains carried a copy of pullulanase gene.
Therefore, neither the art nor the specification provides a sufficient representative number L. crispatus strains to meet the written description requirements.
Breadth of Pretreatment with Antibiotics
The claims of the instant application are drawn to a female subject wherein the subject has not been pretreated with an antibiotic targeting vaginal bacteria.
The claims encompass any kind of treatment in advance would be at any point during the subject’s lifetime.
The specification of the instant application teaches "pretreatment", in the context of the present invention, refers to the subject not having any kind of antibiotic treatment in advance, or simultaneously, as having the composition herein disclosed topically administered to the vagina of said subject. The specification discloses antibiotic that target vaginal bacteria comprise clindamycin, metronidazole, tinidazole, and/or secnidazole (specification page 12). Prior art Kasten (Kasten, Mary Jo. "Clindamycin, metronidazole, and chloramphenicol." Mayo Clinic Proceedings. Vol. 74. No. 8. Elsevier, 1999) reports antibiotics clindamycin and metronidazole target different bacteria and infections and are not limited to bacterial vaginosis (whole document).
Most subjects would have had antibiotics at some point in their life prior to the clinical protocol. The specification does not detail how the inventors determined which subjects were not pretreated with antibiotics targeting vaginal bacteria or any details as to if there was a limit to the time period in which subjects had not been pretreated with antibiotics.
Breadth of Treatment Subjects
The claims of the instant application are drawn to a method of increasing the probability of full-term birth of a female subject at risk of preterm birth.
The claims encompass any female subject who is pregnant with any level of risk of preterm birth or any indicators or causes of the risk of preterm birth.
The specification of the instant application teaches pregnant women at high-risk of preterm birth recruited for LACTIN-V therapy. The specification teaches an embodiment where the subject has a prior history of preterm birth; or a short cervix of 25 mm or less in length; or has a L .iners population of at least 50% in a vaginal fluid sample; or has dysbiosis with a Lactobacillus population of less than 50% in a vaginal fluid sample. However the specification does not explicitly state if the clinical protocol selected subjects with these specific complications nor does it detail how many of which complications were represented in the clinical protocol.
The instant application lacks written description because risk of preterm birth can have many different causes or indicators other than those described in the specification. Medical conditions such as chronic hypertension, gestational diabetes, or lifestyle factors such as smoking or undernutrition are risk indicators of preterm birth. There is not indication in the specification that administering Lactobacillus crispatus cells can increasing the probability of full term birth in all pregnant female subject at risk of preterm birth.
The state of the art teaches various trials that have been run there is uncertainty in outcomes and there is not a consistently reproducible outcome for reducing preterm birth in the art, see Jarde et al above. In the meta-analysis by Jarde et al there are studies where subjects were not at high risk for preterm birth and the studies did not measure a reduction in preterm birth. In addition, Del Barco et al. teach a clinical trial detailed above in which a treatment comprising L. crispatus did not reduce preterm birth and rather had the opposite outcome even though they also selected for patients with increased probability of preterm birth. Neither the art nor the specification teaches a reduction of preterm birth by administration of L. crispatus in all female subjects pregnant at risk
Therefore, for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
Response to Arguments
Applicant's arguments filed 04/22/2026 have been fully considered but they are not persuasive.
Applicant argues that the CTV-05 and SJ-3C strains were deposited in accordance with the Budapest Treaty at the ATCC under the deposit numbers 202225 and PTA-10138.
In response to the argument, and as stated above, if the deposits are made under the terms of the Budapest Treaty, then an affidavit or declaration by Applicant, or a statement by an attorney of record over his or her signature and registration number, stating that the Lactobacillus crispatus cells have been deposited under the Budapest Treaty, that the Lactobacillus crispatus cells will be irrevocably and without restriction or condition released to the public upon the issuance of a patent and that the Lactobacillus crispatus cells will be replaced should they ever become non-viable.
Applicant argues that the Del Barco study was conducted with a L. crispatus strain LBV88, which the Examiner has given no information in regard to its ability to express pullulanase or to produce hydrogen peroxide or to produce L-/D-lactic acid. Applicant argues that claim 1 defines the L. crispatus cells to be used in the claimed method by their three specific functionalities.
In response to the argument, newly cited prior art Laue et al. reports L. crispatus LBV88 has an acidification capacity, produces H2O2 and utilizes glycogen (Abstract). Applicant discloses that a functionally expressed pullulanase gene confers L. crispatus the ability to utilize glycogen (specification page 10). Newly cited prior art Veer et al. reports that among 33 studied L. crispatus strains including strains isolated from vaginal samples with dysbiotic vaginal microbiota, all except two strains carried a copy of pullulanase gene. Examples 3 and 4 disclose administering LACTIN-V (i.e., CTV-05) to pregnant women. However, no examples show the administration of SJ-3C, MV-3A-US and/or MV-lA-US increases the probability of full term birth in a pregnant female subject at risk of preterm birth.
Applicant argues skilled person would recognize that, in the context of using L. crispatus to improve the probability of full-term birth, the requirement of "no antibiotic pretreatment" means no prior treatment of an antibiotic in a fashion (e.g., the nature of antibiotic and time proximity to L. crispatus administration) that could affect a pregnant woman's vaginal microbiota.
In response to the argument, the claims in this application are given their broadest reasonable interpretation and the limitation of pretreatment with an antibiotic does not limit the pretreatment to any specific time or period. The claim encompasses any pretreatment with an antibiotic regardless of the period.
Applicant argues that amended claim 1 now defines the female subject as "at risk for preterm birth," the determination of which is both familiar to those of skill in the art and described in the application.
In response to the argument, the instant application lacks written description because risk of preterm birth can have many different causes or indicators other than those described in the specification. Medical conditions such as chronic hypertension, gestational diabetes, or lifestyle factors such as smoking or undernutrition are risk indicators of preterm birth. There is no indication in the specification that administering Lactobacillus crispatus cells can increasing the probability of full term birth in all pregnant female subject at risk of preterm birth.
Conclusion
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARY A CRUM whose telephone number is (571)272-1661. The examiner can normally be reached M-F 8:00-5:00 CT with alternate Fridays off.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, LOUISE W HUMPHREY can be reached at 571-272-5543. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MARY A CRUM/ Examiner, Art Unit 1657
/THANE UNDERDAHL/ Primary Examiner, Art Unit 1699
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