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 Claims
The preliminary amendment on 3/29/2024 is acknowledged. Claims 1-18 are pending and examined herein.
Abstract
The abstract of the disclosure does not commence on a separate sheet in accordance with 37 CFR 1.52(b)(4) and 1.72(b). A new abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text.
Specification
The use of the term Lyoguard® on page 36 of the specification, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term. Lyoguard® is registered and should not use ™.
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.
The disclosure is objected to because it contains an embedded hyperlink on page 10 of the specification and/or other form of browser-executable code. 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.
Biological Deposit
Claims 1-18 are 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 1-18 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.
Claim Rejections - 35 USC § 112
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 5 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 further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 1 teaches “A method fo--r increasing the probability of full-term birth in a pregnant female subject”. Claim 5 teaches “The method of claim 1, wherein the subject is planning a pregnancy”. If a subject is planning a pregnancy, then the subject is not pregnant or they or their medical care team do not know they are pregnant, a subject could be planning a pregnancy at any point in their life far outside any time they are pregnant, for example, 30 years before they are pregnant. Thus claim 5 fails to include the limitation of being a pregnant subject from claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Written Description
Claims 1-18 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
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 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.
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) 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) “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.
Therefore, neither the art nor the specification provides a sufficient representative number L. crispatus strains to meet the written description requirements.
Breadth of Time
The claims of the instant application are drawn to a method of increasing the probability of full-term birth of a female subject that is planning a pregnancy or pregnant.
The claims encompass any female subject at any point in a subject’s life when they are sentient enough to plan a pregnancy until menopause and all 3 trimesters of pregnancy.
The specification of the instant application teaches: following enrollment at or as close to 14 weeks as possible, the subject will be given a "loading phase" of 5 daily doses of L. crispatus CTV-05 (LACTIN-V), followed by a "maintenance phase" of 6 weekly doses, for a total of 11 doses. This treatment regimen is entirely encompassed within the 2nd trimester of pregnancy.
This is lacks support because one of skill in the art cannot envision how long the treatment affect would last.
The state of the art teaches there is a lack of studies of preterm birth prevention by probiotics as such the art is not well versed in determining what factors will lead to effective colonization of the vaginal microbiome and improve clinical outcomes. One must look to the nearest reasonable examples in the art to determine what variance there is in expected outcomes. Jarde et al. (Pregnancy outcomes in women taking probiotics or prebiotics: a systematic review and meta-analysis, BMC Pregnancy and Childbirth, 2018) executed a meta-analysis and review of pregnancy outcomes in women taking probiotics which analyzed 27 independent studies. On page 9 Jarde et al. teaches “Overall, we found no evidence of either harm or benefit of probiotics or prebiotics on preterm birth” The teaching of Jarde et al demonstrates that of the 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.
Del Barco et al. teach a clinical trial detailed above in which “the patients started the intervention with two vaginal capsules of the probiotic or placebo until 36.6 weeks of gestation. The maximum treatment duration was from 24.0 to 36.6 weeks of gestation.” This represents an example of treatment starting in the late 2nd trimester through the late 3rd trimester which has a negative outcome. One of skill in the art cannot envision that treatment that starts later than 24 weeks would be effective.
The instant specification states that bacterial vaginosis is associated with preterm birth on page 2 and as such studies of bacterial vaginosis provide art which can enable one to envision what may affect the outcomes of treatment. In the art Cohen et al conducted a trial of LACTIN-V to prevent recurrence of bacterial vaginosis, this study is relevant to the instant application because it uses the same strain and composition and delivery method. During this trial they measured incidence and concentration of L. crispatus CTV-05 out to 14 weeks post treatment. A significant decline in participants with detectable L. crispatus CTV-05 is observed at 14-week post treatment time point (which is 24 weeks since the start of treatment) in Figure 2 of the reference. This evidence presented creates uncertainty in how long after treatment L. crispatus CTV-05 would remain colonized in the vagina and what factors influence persistence of the strain. One of skill in the art cannot envision given that time frame that L. crispatus would persist significantly longer than 18 weeks past the final administration of L. crispatus CTV-05 in the instant application. Therefore, the inventors lack written description for the full breadth of the timeframe of the claims. The treatment starts in the second trimester and ends 18 weeks before the expected end of pregnancy. This does not include a time frame long enough to cover a treatment that would begin and end in the first trimester which is encompassed in claim 1 or at any point prior to pregnancy when a subject may be planning a pregnancy as in claim 5 of the instant application.
Figure 2 of Cohen et al. provided below for convenience.
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Taken together the art demonstrates it is not known how long bacteria will persist in the vagina without continued application past what is experimentally demonstrated. The inventors of the instant application demonstrate set of specific conditions in which they measured a reduction in preterm birth in the 2nd trimester. Therefore, neither the art nor the specification teaches efficacy of reducing preterm birth over the lacks support for the time range claimed by the applicants.
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.
The claims encompass the 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.
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 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.
The claims encompass any female subject whom is pregnant or planning a pregnancy.
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 any female subject planning a pregnancy or pregnant may not be at high risk for 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.
Therefore, neither the art nor the specification teaches a reduction of preterm birth by administration of L. crispatus in all female subjects pregnant or planning a pregnancy.
Relevant Information for Written Description
Therefore, the specification provides insufficient written description to support the genus encompassed by the claim. Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that
"applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
The skilled artisan cannot envision the detailed chemical structure of the encompassed polypeptides, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The nucleic acid and/or protein itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that:
...To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc. , 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli , 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2datl966.
The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art-recognized correlation or relationship between the structure of the invention and its function (see MPEP 2163). A patent specification must set forth enough detail to allow a person of ordinary skill in the art to understand what is claimed and to recognize that the inventor invented what is claimed. In the case of DNA, an adequate written description requires a precise definition, such as by structure, formula, chemical name, or physical properties, not a mere wish or plan for obtaining the claimed chemical invention (see Lilly, 119 F.3d at 1566 (quoting Fiers, 984 F.2d 15 1171 ). Because the specification does not describe the amino acid sequences nor any core structures for potentially numerous different antibody amino acid sequences which would have the recited functions, one of skill in the art would reasonably conclude that applicant was not in possession of the claimed genus of all anti-CD122 antibodies which bind to CD122 and modulate immune function and ADA formation.
Therefore, neither the art nor the specification provides a sufficient representative number of antibodies or a sufficient structure-function correlation to meet the written description requirements.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the "written description" requirement is broader than to merely explain how to "make and use"; the Applicant must convey with reasonable clarity to those skilled in the art, that as of the filing date sought, he or she was in possession of the invention. The invention is for purposes of the “written description” inquiry, whatever is now claimed. See Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).
Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed.
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.
Conclusion
No claims are allowed.
Inquiry Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RUDOLPH EDWARD SLOUP Jr. IV Ph.D. whose telephone number is (571)272-7899. The examiner can normally be reached Monday to Friday, 9am to 4pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor Vanessa Ford can be reached at 571-272-0857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/RUDOLPH EDWARD SLOUP Jr. IV Ph.D./ Examiner, Art Unit 1645
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674