DETAILED CORRESPONDENCE
Status of the Application
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant’s submission filed on 11/25/2025 has been entered.
Claims 1-10, 16-19 and 23-24 are pending in this application.
Applicant’s amendment to the claims filed 11/25/2025 is acknowledged. This listing of the claims replaces all prior versions and listings of the claims.
Applicant’s remarks filed on 11/25/2025 in response to the final rejection mailed on 08/28/2025 is acknowledged and has been fully considered.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Election
The elected subject matter is:
Invention II, corresponding to claims 16-19 and new claims 23-24, drawn to methods for balancing the vaginal microbiome, treating symptoms related to vaginal infection, and balancing vaginal pH, and
Species (B2), administration to a subject without bacterial vaginosis,
elected in the reply filed 10/31/2023.
Claims 1-10 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claim 17 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claims 16, 18-19 and 23-24 are being examined on the merits only to the extent the claims read on the elected subject matter as set forth above.
Claim Rejections - 35 USC § 112(b)
Claims 16 and 18-19 are newly rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
The instant rejection is necessitated by claim amendment.
Claim 16 (claims 18-19 dependent therefrom) is rejected for the recitation “the at least one symptom” in line 4. There is insufficient antecedent basis for this limitation in the claim.
Claim Rejections - 35 USC § 103
The rejection of claims 11-14 and 21-22 under 35 U.S.C. 103 as being unpatentable over Acosta et al. (WO 2022/185121 A1; cited in the IDS submitted on 03/17/2023; herein referred to as Acosta) in view of Komoroski et al. (U.S. Patent No. 8,586,061 B2; cited on the Form PTO-892 mailed 11/17/2023; herein referred to as Komoroski) is withdrawn in view of the cancelation of the claims.
The rejection of claims 16 and 18-19 under 35 U.S.C. 103 as being unpatentable over Acosta in view of Komoroski as applied to claims 11-14 and 21-22 above, and further in view of Livengood et al. (“Bacterial Vaginosis: An Overview for 2009”, Reviews in Obstetrics and Gynecology, Vol 2 (1), 2009; cited on the Form PTO-892 mailed 11/17/2023; herein referred to as Livengood) is withdrawn in view of the amendment to claim 16 to recite the limitations regarding the inclusion of lactoferrin in the oral multi-component formulation.
Claims 16, 18-19 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Acosta in view of Komoroski, Livengood and Longoni et al. (WO 2010/081126; cited in IDS submitted on 03/17/2023; herein referred to as Longoni).
The instant rejection is maintained from a previous office action and has been modified to address the amendments to the claims.
Claim 16 is drawn to a method of treating, preventing, or ameliorating vaginal odor, the method comprising:
identifying the at least one symptom in a subject;
administering to the subject an oral multi-component formulation (OMCF) to treat, prevent or ameliorate vaginal odor, wherein the OMCF comprises:
a probiotic composition layer, wherein the probiotic composition layer comprises an amount of at least two Lactobacillus species and an amount of lactoferrin;
a supplement composition layer, wherein the supplement composition layer comprises an amount of at least one nutritional supplement ingredient, wherein the at least one nutritional supplement ingredient comprises an amount of folic acid, folate, or a pharmaceutically acceptable sale thereof; and
a middle barrier layer disposed between the probiotic composition layer and the supplement composition layer, wherein the probiotic composition layer and the supplement composition layer are positioned on opposing sides of the middle barrier layer.
Acosta describes pharmaceutical compositions used to treat inflammation in the female genitourinary tract that arise from a dysbiotic microbiota. Acosta discusses inflammation is related to the imbalance of resident microbes in the genitourinary tract, wherein the pH of the environment is changed from the healthy range of 3.8 – 4.5 that is normally unfavorable to pathogenic growth, and depending on the pathogenic organism that grows, these infections can develop into bacterial vaginosis, vaginal candidiasis, trichomoniasis, or combinations thereof [para 0003], and the described compositions are effective in the treatment of diseases, symptoms and/or disorders of the female urogenital tract [para 0007]. Therefore Acosta connects the imbalance of pH in the vaginal environment with the onset of infections that develop into bacterial vaginosis, for example, and therefore describes compositions effective for treating such issues.
Regarding claim 16, Acosta teaches "a method of treating dysbiosis in the female genitourinary tract of a human subject comprising administering to a subject in need of such treatment an effective amount of a pharmaceutical composition comprising a substantially complete vaginal microbiota preparation (SCVMP)” [para 00069], wherein such treatments “may be administered using different routes of administration and dosage forms, such as orally (e.g., as a pill) or topical (e.g., as a gel)” [para 000197], and wherein dysbiosis is defined as “a perturbation of the vaginal homeostasis … a dysbiotic vaginal microbiota will generally result in increased pH relative to a healthy microbiota, e.g., a pH above 4.5, e.g., a pH of 5.0, 5.5, 6.0, 6.5, 7.0 or higher” [para 000301]. Acosta further teaches “Restoring a healthy vaginal microbiota balance may comprise achieving a pH of the vaginal tract of about pH 3.5 to 4.5. Preferably, the administration of the one or more species of lactic acid producing bacteria restores the vaginal pH to about 3.7 to about 4.2, more preferably to about 3.8 to about 4.0” [para 00064]. These teachings of Acosta are considered to correspond to the identification of at least one symptom as a dysbiotic vaginal microbiota producing an increased pH relative to a healthy microbiota, and correspond to the administration of an oral formulation to treat the dysbiosis.
Regarding claim 16 and the limitations of the OMCF with probiotic composition layer comprised of Lactobacillus species, Acosta teaches a “substantially complete vaginal microbiota preparation comprises further lactobacilli other than Lactobacillus crispatus, Lactobacillus iners, Lactobacillus jensenii, or Lactobacillus gasseri, wherein the further Lactobacillus species include, e.g., Lactobacillus acidophilus, Limosilactobacillus fermentum (formerly known as Lactobacillus fermentum), Lacticaseibacillus casei (formerly known as Lactobacillus casei), and Lacticaseibacillus rhamnosus (formerly known as Lactobacillus rhamnosus). As used herein, Limosilactobacillus fermentum, Lacticaseibacillus casei, Lacticaseibacillus rhamnosus are referred to as Lactobacillus and are included in the meaning of Lactobacillus” [para 000116], which is considered to correspond to a formulation comprising at least two Lactobacillus species. Acosta additionally teaches the preparation may be formulated as a pharmaceutical composition in the form of a capsule [para 00056], and that any therapeutic described can be considered for a pharmaceutical composition with the SCVMP or a combination therapy, wherein administration can occur in different dosage forms such as orally (e.g., a pill) [para 000196]. As Acosta describes the administration of an SCVMP comprising multiple Lactobacillus species, the formulation of an SCVMP as a capsule, and the administration of combination therapies that include oral dosage forms (e.g., a pill), the teachings of Acosta are considered to correspond to an OMCF comprising at least two Lactobacillus species.
Regarding claim 16 and the inclusion of a nutritional supplement, Acosta teaches bacterial species that display promising in vitro results may not colonize in vivo and provide the desired therapeutic effect, or the effect is transient as the strains delivered are not able to collectively adapt to provide maintained colonization over time [para 0005]. As Acosta teaches compositions that are effective in the treatment of diseases, symptoms and/or disorders of the female supplement urogenital tract, including effective colonization of the vaginal niche [para 0007], Acosta is considered to connect the effective colonization of Lactobacillus species in the vaginal niche with providing the desired therapeutic effect of the described compositions. While Acosta does not explicitly teach the inclusion of a “nutrient supplement”, Acosta teaches compositions can additionally comprise prebiotics such as inulin to increase the growth of the bacteria [paras 000182-000183], thiosulfate that would potentiate the effect of the Lactobacillus [para 000187], and carbon sources for the microbiota such as sodium alginate [para 000210], and one of skill in the art would expect each of these as inferred by Acosta to increase the survival and proliferation of the Lactobacillus in the composition, and thereby increase the effective amount of the Lactobacillus species delivered. As the instant specification does not specifically define a nutritional supplement, but instead gives examples of nutritional supplements to include fatty acids, amino acids, vitamins, dietary minerals, metabolic intermediates and plant extracts [paras 0016-0019], these additional components of Acosta are considered nutritional supplements as recited by the claim.
Regarding claim 16 and the use of folic acid, folate or a pharmaceutically acceptable salt thereof as the nutritional supplement, Acosta teaches the use of folate salts to maintain low pH [para 000173]. As folate is listed as an example of a nutritional supplement in [para 0017] of the instant specification, the folate of Acosta is also considered a nutrient supplement as recited in the claim.
Acosta does not teach the limitations of the OMCF regarding the different layers, the inclusion of lactoferrin and folate in specific layers, and the treatment of the specific symptom of vaginal odor.
Livengood reviews bacterial vaginosis [title], and discloses the essential manifestations of bacterial vaginosis are well established as the loss of the normal bacterial population of the vagina and their replacement by other species [abstract], therein describing dysbiosis.
Regarding claim 16, Livengood teaches “the classic symptom of BV [bacterial vaginosis] is an odor that is usually described as 'fishy'” [p 30, column 3, para 1], as well as that increased vaginal discharge is a more frequent but less specific symptom of BV [p 30, col 3, para 1]. As the method of Acosta can be used for treatment of dysbiosis associated with bacterial vaginosis, and a vaginal odor and increased vaginal discharge are symptoms of bacterial vaginosis, the method of Acosta of treating dysbiosis associated with BV is considered to encompass the treatment of symptoms associated with BV such as vaginal odor, as taught by Livengood.
Komoroski describes compositions and methods for combination therapy, including multiple unit dosage forms with both therapeutic agents and nutritional supplements, wherein the combination therapy is useful for restoring a nutrient depletion associated with a particular disease state [abstract], or resulting from the use of the formulation for the treatment of the disease [para 0003].
Regarding claim 16 and the limitation of an OMCF comprising a probiotic composition layer, a middle barrier layer, and a supplement composition layer, wherein the middle barrier layer (MBL) separates the probiotic composition layer (PCL) from the supplement composition layer (SCL), Komoroski describes compositions and methods for combination therapy, comprising multiple unit dosage with a therapeutic agent and a nutritional supplement [abstract], wherein “the invention disclosed herein includes a multiple unit dosage form for oral administration comprising an effective amount of a therapeutic agent, a barrier layer, and a nutritional supplement, wherein the therapeutic agent and the nutritional supplement are formulated as a single dose. In certain aspects of the invention, the barrier layer is located between the therapeutic agent and the nutritional supplement and prevents interaction between said therapeutic agent and said nutritional supplement” [para 0008, Figure 1]. As the instant application does not define the term probiotic or probiotic composition layer, but rather uses the terms synonymously with Lactobacillus species, under the broadest reasonable interpretation a probiotic composition layer is interpreted to encompass probiotics comprised of at least Lactobacillus species.
Regarding claim 16 and the limitation of a MBL separating the PCL from the SCL, wherein the SCL contains at least one nutritional supplement ingredient, Komoroski teaches “a multiple unit dosage form for oral administration comprising an effective amount of a therapeutic agent, a barrier layer, and a nutritional supplement, wherein the therapeutic agent and the nutritional supplement are formulated as a single dose. In certain aspects of the invention, the barrier layer is located between the therapeutic agent and the nutritional supplement and prevents interaction between said therapeutic agent and said nutritional supplement” [para 0009, Figure 1]. Komoroski teaches “the phrase "therapeutic agent" is intended to have its broadest possible interpretation and refers to any therapeutically active substance that is delivered to a bodily conduit of a living being to produce a desired, usually beneficial, effect” [para 0009]. Furthermore, Komoroski teaches that the MBL “is comprised of a controlled release, delayed release, or enteric coating to control or delay the release of the inner contents of the multiple unit dosage form. The middle layer advantageously improves the rate of absorption of the therapeutic agent and/or nutritional supplement. In one embodiment, the middle barrier layer increases the efficacy of the therapeutic agent and/or nutritional supplement” [para 00027].
Regarding claim 16 and the limitation of a nutritional supplement, Komoroski teaches the inclusion of nutritional supplements in the composition, wherein nutritional supplement “is intended to be afforded its broadest possible interpretation and refers to a composition that … contains one or more of the following ingredients: a vitamin, a mineral, an herb or other botanical … and a concentrate, metabolite, constituent, extract, or combination of any of the above … Nutritional supplement further includes dietary minerals such as, for example … sodium, [and] sulfur” [col 5, para 2]. In view of the teaching of Komoroski of the inclusion of a nutritional supplement in a separate layer from the therapeutic agent, wherein nutritional supplements include vitamins, and the teaching of Acosta to include the vitamin folic acid the above described treatments, one of skill in the art would reasonably conclude that the OMCF could be adapted for use in the Acosta method by incorporating the Lactobacillus species and folic acid into respective layers of the Komoroski formulation.
Longoni describes compositions of probiotics, prebiotics, mineral salts and lactoferrin for the effective colonization of probiotic administration [abstract]. These compositions are disclosed to have anti-inflammatory effects, and can be used for the preparation of nutritional supplements and pharmaceutical-grade products.
Regarding claim 16 and the limitations regarding lactoferrin, Longoni notes the challenges in administering probiotics, that “to be effective, said probiotics must not only survive manufacturing processing, packaging and storage conditions, but also then must survive transit through the gastrointestinal tract so the probiotic material remains viable to have a positive health effect” [p 3, lines 1-3]. Longoni therefore teaches as a solution to this problem that “compositions comprising a probiotic … and a carrier material comprising prebiotic materials, mineral salts, and lactoferrin will not only have improved and/or enhanced survival of the probiotic species, but also performs the effective colonization of the probiotic components administered with enteric consequences of common dysbioses of the digestive tract caused by stress, incorrect dietary habits, antibiotic treatments, illness and the like” [p 2, line 4-9]. As Longoni teaches the inclusion of lactoferrin to enhance survival of probiotic species for successful colonization and implied treatment of dysbiosis, one of skill in the art would be motivated to include lactoferrin with the Lactobaciillus species for the treatment of dysbiosis taught by Acosta above, and would therefore be expected to include the lactoferrin with the probiotic in the OMCF of Komoroski.
In view of Acosta, Livengood, Komoroski, and Longoni, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Acosta by using an OMCF, as taught by Komoroski, including lactoferrin, as taught by Longoni, for the treatment of vaginal odor associated with dysbiosis and bacterial vaginosis, as taught by Livengood, to arrive at the claimed invention.
One of ordinary skill in the art would have been motivated to modify the method of Acosta by using an OMCF, because Komoroski teaches the use of an OMCF comprising a middle barrier layer between a layer comprising a therapeutic agent and a layer comprising a nutritional supplement advantageously improves the rate of absorption of the therapeutic agent and/or nutritional supplement.
One of ordinary skill in the art would have been motivated to modify the method of Acosta by using lactoferrin in probiotic formulations, because Longoni teaches the use of lactoferrin improves and/or enhances survival of the probiotic species as well as the effective colonization of the probiotic components administered.
One of ordinary skill in the art would have been motivated to modify the method of Acosta by using it to treat vaginal odor vaginal odor associated with dysbiosis and bacterial vaginosis, because Acosta teaches the treatment of vaginal dysbiosis and Livengood teaches vaginal odor is a symptom attributed to bacterial vaginosis that arises from vaginal dysbiosis.
One of ordinary skill in the art would have had a reasonable expectation of success, because Acosta and Komoroski teach methods of producing orally administered formulations comprised of therapeutic agents and nutrient supplements, Acosta and Livengood discuss treatments for bacterial vaginosis, and Acosta and Longoni discuss components of probiotic formulations that enhance survival of said probiotics and therefore effectiveness in treating dysbiosis.
Regarding claim 18, Acosta teaches “a method of treating dysbiosis in the female genitourinary tract of a human subject”, wherein “dysbiosis can be associated with an infection”, and “the infection can be … vaginal candidiasis” [para 00069].
Regarding claim 19, Acosta teaches a “substantially complete vaginal microbiota preparation comprises further lactobacilli other than Lactobacillus crispatus, Lactobacillus iners, Lactobacillus jensenii, or Lactobacillus gasseri, wherein the further Lactobacillus species include, e.g., Lactobacillus acidophilus, Limosilactobacillus fermentum (formerly known as Lactobacillus fermentum), Lacticaseibacillus casei (formerly known as Lactobacillus casei), and Lacticaseibacillus rhamnosus (formerly known as Lactobacillus rhamnosus). As used herein, Limosilactobacillus fermentum, Lacticaseibacillus casei, Lacticaseibacillus rhamnosus are referred to as Lactobacillus and are included in the meaning of Lactobacillus” [para 000116], wherein the formulation comprises at least two species of Lactobacillus, and include further lactobacilli such as Lactobacillus acidophilus and Lactobacillus rhamnosus.
Regarding claim 23, the limitations of the instant claim share considerable overlap with the limitations of claim 16, with the exceptions that (1) the instant claim does not recite the OMCF that is recited in claim 16, and (2) the instant claim recites specific Lactobacillus species to be included in the instant method. In view of these similarities, the combined method of Acosta, Livengood, Komoroski and Longoni as described above is considered to correspond to a method of treating, preventing or ameliorating vaginal odor comprising identifying a subject in need thereof, administering an oral formulation to prevent said vaginal odor, wherein the oral formulation comprises at least two Lactobacillus species, lactoferrin and folic acid, folate or a pharmaceutically acceptable salt thereof as described in the rejection of claim 16 above, wherein the formulation comprises at least two species of Lactobacillus that include Lactobacillus acidophilus and Lactobacillus rhamnosus [para 000116 of Acosta]. As the oral formulation is recited to comprise an amount of L. acidophilus and an amount of L. rhamnosus, the claimed combination is interpreted to include other unnamed components, and therefore the combined teachings of Acosta, Livengood, Komoroski and Longoni are considered to correspond to the limitations in the claims.
Therefore, the invention of claims 16, 18-19 and 23 would have been obvious to one of ordinary skill in the art before the effective filing date.
Claim 24 is newly rejected under 35 U.S.C. 103 as being unpatentable over Acosta, Komoroski, Livengood, and Longoni as applied to claims 16, 18-19 and 23 above, and further in view of Ya et al. (Am J Obstet Gynecol, 2010, 203:e1; cited on the attached Form PTO-892; herein referred to as Ya).
The instant rejection is necessitated by claim amendment.
Claim 24 is drawn to the method of claim 23, wherein the amount of L. acidophilus and the amount of L. rhamnosus are present in a ratio of 4:1.
The teachings of Acosta, Komoroski, Livengood, and Longoni as applied to claims 16, 18-19 and 23 are discussed above. These references do not teach the amount of L. acidophilus and the amount of L. rhamnosus are present in a ratio of 4:1.
Ya relates to the efficacy of vaginal probiotic capsules for recurrent vaginosis [title], and discusses the standard cure for BV is metronidazole or clindamycin, which have low success rates and high recurrence rates as well as reduce the metabolic activity of vaginal bacteria, and therefore the need to explore new BV therapies exists wherein Lactobacilli present an alternative option for BV prevention [p e1, col 2, paras 2-3].
Regarding claim 24, Ya teaches the administration of probiotic capsules containing 6.8 x 109 CFU L. rhamnosus and 0.4 x 109 CFU L. acidophilus to healthy women between 18-55 years old with a history of >2 BV episodes the previous year and had no antibiotic treatment within the 1 week of the study [p e2, col 1, para 3 to col 2, para 1], wherein the probiotic treatment resulted in a reduction of malodor throughout the trial period within the test group and compared to the control [Table 2]. While Ya does not teach the ratio of 4:1 L. acidophilus to L. rhamnosus as recited in the claim, MPEP 2144.05.II.A states where 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. Ya additionally suggests the success of the probiotic is attributed to the dosage of Lactobacillus used which likely overwhelmed the vaginal microbiota to inhibit or destroy pathogenic bacteria causing said symptoms [p e5, col 1, para 2], thereby suggesting Lactobacillus dosage as a result effective variable, which is a variable that achieves a recognized result according to MPEP 2144.05.II.B, which effects the outcome of reducing the symptom of malodor.
In view of Ya, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined method of Acosta, Livengood, Komoroski, and Longoni by altering the ratio of L. acidophilus and L. rhamnosus, to achieve the claimed ratio of bacterial species, as Ya establishes the general conditions of the administration of 6.8 x 109 CFU L. rhamnosus and 0.4 x 109 CFU L. acidophilus to reduce vaginal odor in patients, and suggests the result effective variable of Lactobacillus dosage as responsible for the observed reduction in vaginal odor. One of ordinary skill in the art would have had a reasonable expectation of success, because Acosta and Ya teach methods of treating symptoms related to vaginal dysbiosis using L. acidophilus and L. rhamnosus.
Therefore, the invention of claim 24 would have been obvious to one of ordinary skill in the art before the effective filing date.
Response to Remarks. Beginning on page 2 of Applicant’s response to the rejections under 35 USC 103; Applicant in summary contends the formulation in Example 1 of the specification exhibits an unexpected advantage over the closest prior art of Exhibit A (Russo et al., Arch Gynecol Obstet, 2017, 298:139; cited on the IDS filed 11/25/2025); Applicant further contends the formulation required by amended claim 16 is commensurate in scope with the formulation of Example 1 in the specification; Applicant further contends new claims 23-24 recite the oral formulation identical or equivalent to Example 1 in the specification which exhibits unexpected higher efficacy than the closest prior art.
Applicant’s remarks are considered and found not convincing.
Regarding the argument of “an unexpected advantage” of the formulation in Example 1 over the closest prior art (recited in point (a) on page 3 of Applicant’s remarks), MPEP 2145.II states the recognition of latent properties in the prior art does not render nonobvious an otherwise known invention, and the recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.
Applicant’s assertion that Example 1 of the specification exhibits an unexpected advantage and/or higher efficacy over the prior art is being considered an allegation of unexpected results.
Regarding the allegation that Example 1 of the specification exhibits an unexpected advantage over the prior art, Applicant contends the formulation of the prior art resulted in no statistical difference in the reduction of vaginal odor compared to placebo citing Figure 2, whereas the formulation of Example 1 resulted in significant reductions in vaginal odor at weeks 2, 4, 6, 8, 10 and 12 (p<0.001) [paras 0047-0049 of the instant specification]. As the significance reported in the prior art is derived from a comparison of treatment vs. placebo groups at each timepoint (see Fig. 2 legend), and the significance disclosed in the specification is derived from comparison of symptoms at timepoints compared to symptoms at the onset of the study, the results of the statistical analyses between Example 1 and the prior art are not directly comparable. Put another way, the significance determinations by each study were based both on different criteria and different data, and therefore the lack of significance in one study and the presence of significance in another study are not directly comparable. Example 1 of the instant specification shows a significant reduction in vaginal odor among evaluated study participants compared to their initial evaluated vaginal odor at the onset of the study, but there is no comparison to a placebo group at each timepoint. The study of the prior art shows no significant reduction in vaginal odor at the final timepoint of the treatment group compared to the placebo group at the same timepoint, but there is no statistical evaluation of the change in vaginal odor of study participants compared to their initial evaluated vaginal odor at the onset of the study. According to MPEP 716.02(b).I, the burden is on Applicant to establish results are unexpected and significant, and the evidence relied upon should establish that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance. Therefore, while Example 1 of the specification indeed shows a significant reduction in vaginal odor over time, the allegations that this result is significant over the prior art is not convincing, as the significance determinations between the studies are not directly comparable, and the prior art cited by Applicant still indicates a reduction in vaginal odor over time from participants taking the probiotic supplement. As such, Applicant has not established the results are both unexpected and significant, and the data proffered by Applicant does not establish the differences in results are in fact unexpected and unobvious and of both statistical and practical significance. Therefore Applicant’s allegations of unexpected results do not satisfy the requirements of MPEP 716.02(b).I.
Regarding the assertion that amended claim 16 is commensurate in scope with the formulation of Example 1 in the specification, this assertion is being considered an allegation of unexpected results to rebut the rejection of claims 16 and 18-19 for the reasons set forth above regarding Example 1 compared with the closest prior art. According to MPEP 716.02(d), unexpected results must be commensurate in scope with the claimed invention. As the formulation of Example 1 in the specification from which the alleged unexpected results are derived comprises Lactobacillus acidophilus, Lactobacillus rhamnosus, 400 mcg folate, and 50 mg lactoferrin, the unexpected results are not considered commensurate in scope with the invention of claim 16 that is drawn (in relevant part) to a method of treating, preventing or ameliorating vaginal odor comprising administering a formulation comprising at least two Lactobacillus species, an amount of lactoferrin, and an amount of folic acid, folate, or a pharmaceutically acceptable salt thereof. Put another way, the scope of claim 16 corresponds to the administration of a formulation comprising at least any two of all Lactobacillus species, any amount of lactoferrin, and any amount of folate, whereas the scope of the formulation Example 1 of the specification corresponds to only two Lactobacillus species and single dose each of lactoferrin and folate. Therefore Applicant’s allegations of unexpected results do not satisfy the requirements of MPEP 716.02(d).
Regarding the assertion that new claims 23-24 recite the oral formulation identical or equivalent to Example 1 in the specification which exhibits unexpected higher efficacy than the closest prior art: as discussed above and repeated here, MPEP 716.02(b).I states the burden is on Applicant to establish results are unexpected and significant, and the evidence relied upon should establish that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance. Therefore, while Example 1 of the specification indeed shows a significant reduction in vaginal odor over time, the allegations that this result is significant over the prior art is not convincing, as the significance determinations between the studies are not directly comparable, and the prior art cited by Applicant still indicates a reduction in vaginal odor over time from participants taking the probiotic supplement. As such, Applicant has not established the results are both unexpected and significant, and the data proffered by Applicant does not establish the differences in results are in fact unexpected and unobvious and of both statistical and practical significance. Therefore Applicant’s allegations of unexpected results do not satisfy the requirements of MPEP 716.02(b).I.
Therefore, the applicant's remarks and allegations of unexpected results having been fully considered are not found persuasive to rebut a prima facie case of obviousness.
Double Patenting
The rejection of claims 11-14, 21 and 22 on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 8,586,061 (cited on the Form PTO-892 mailed 11/17/2023; hereafter “patent”) in view of Acosta is withdrawn in view of the cancelation of the claims.
The rejection of claims 16 and 18-19 on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 8,586,061 in view of Acosta as applied to claims 11-14, 21 and 22 above, and further in view of Livengood is withdrawn in view of the amendment to claim 16 to recite the limitations regarding the inclusion of lactoferrin in the OMCF.
Claims 16, 18-19 and 23 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 8,586,061 in view of Acosta, Livengood, and Longoni.
The instant rejection is maintained from the previous Office Action and any newly recited portions are necessitated by claim amendment.
Regarding instant claim 16 and the limitations of an OMCF comprising a PCL, an SCL, and an MBL that separates the PCL from the SCL, claim 1 of the patent recites “a multiple unit dosage form for oral administration comprising an effective amount of insulin, a barrier layer, and a nutritional supplement… wherein said barrier layer is located between said insulin and said nutritional supplement”.
The claims of the patent do not recite a method of treating, preventing, or ameliorating vaginal odor, the method comprising identifying the at least one symptom in a subject; administering to the subject an OMCF to treat, prevent or ameliorate vaginal odor; a probiotic composition comprising an amount of at least two Lactobacillus species and an amount of lactoferrin; and a supplement composition layer comprising folic acid, folate, or a pharmaceutically acceptable sale thereof.
Acosta describes pharmaceutical compositions used to treat inflammation in the female genitourinary tract that arise from a dysbiotic microbiota. Acosta discusses inflammation is related to the imbalance of resident microbes in the genitourinary tract, wherein the pH of the environment is changed from the healthy range of 3.8 – 4.5 that is normally unfavorable to pathogenic growth, and depending on the pathogenic organism that grows, these infections can develop into bacterial vaginosis, vaginal candidiasis, trichomoniasis, or combinations thereof [para 0003], and the described compositions are effective in the treatment of diseases, symptoms and/or disorders of the female urogenital tract [para 0007]. Therefore Acosta connects the imbalance of pH in the vaginal environment with the onset of infections that develop into bacterial vaginosis, for example, and therefore describes compositions effective for treating such issues.
Regarding instant claim 16, Acosta discloses "a method of treating dysbiosis in the female genitourinary tract of a human subject comprising administering to a subject in need of such treatment an effective amount of a pharmaceutical composition comprising a substantially complete vaginal microbiota preparation (SCVMP)” [para 00069], wherein such treatments “may be administered using different routes of administration and dosage forms, such as orally (e.g., as a pill) or topical (e.g., as a gel)” [para 000197], and wherein dysbiosis is defined as “a perturbation of the vaginal homeostasis … a dysbiotic vaginal microbiota will generally result in increased pH relative to a healthy microbiota, e.g., a pH above 4.5, e.g., a pH of 5.0, 5.5, 6.0, 6.5, 7.0 or higher” [para 000301]. Acosta further discloses “Restoring a healthy vaginal microbiota balance may comprise achieving a pH of the vaginal tract of about pH 3.5 to 4.5. Preferably, the administration of the one or more species of lactic acid producing bacteria restores the vaginal pH to about 3.7 to about 4.2, more preferably to about 3.8 to about 4.0” [para 00064]. These disclosures of Acosta are considered to correspond to the identification of at least one symptom as a dysbiotic vaginal microbiota producing an increased pH relative to a healthy microbiota, and correspond to the administration of an oral formulation to treat the dysbiosis.
Regarding instant claim 16 and the limitations of the oral multi-component formulation with probiotic composition layer comprised of Lactobacillus species, Acosta discloses a “substantially complete vaginal microbiota preparation comprises further lactobacilli other than Lactobacillus crispatus, Lactobacillus iners, Lactobacillus jensenii, or Lactobacillus gasseri, wherein the further Lactobacillus species include, e.g., Lactobacillus acidophilus, Limosilactobacillus fermentum (formerly known as Lactobacillus fermentum), Lacticaseibacillus casei (formerly known as Lactobacillus casei), and Lacticaseibacillus rhamnosus (formerly known as Lactobacillus rhamnosus). As used herein, Limosilactobacillus fermentum, Lacticaseibacillus casei, Lacticaseibacillus rhamnosus are referred to as Lactobacillus and are included in the meaning of Lactobacillus” [para 000116], which is considered to correspond to a formulation comprising at least two Lactobacillus species. Acosta additionally discloses the preparation may be formulated as a pharmaceutical composition in the form of a capsule [para 00056], and that any therapeutic described can be considered for a pharmaceutical composition with the SCVMP or a combination therapy, wherein administration can occur in different dosage forms such as orally (e.g., a pill) [para 000196]. As Acosta describes the administration of an SCVMP comprising multiple Lactobacillus species, the formulation of an SCVMP as a capsule, and the administration of combination therapies that include oral dosage forms (e.g., a pill), the disclosure of Acosta are considered to correspond to an oral multi-component formulation comprising at least two Lactobacillus species.
Regarding instant claim 16 and the inclusion of a nutritional supplement, Acosta discloses bacterial species that display promising in vitro results may not colonize in vivo and provide the desired therapeutic effect, or the effect is transient as the strains delivered are not able to collectively adapt to provide maintained colonization over time [para 0005]. As Acosta discloses compositions that are effective in the treatment of diseases, symptoms and/or disorders of the female supplement urogenital tract, including effective colonization of the vaginal niche [para 0007], Acosta is considered to connect the effective colonization of Lactobacillus species in the vaginal niche with providing the desired therapeutic effect of the described compositions. While Acosta does not explicitly disclose the inclusion of a “nutrient supplement”, Acosta discloses compositions can additionally comprise prebiotics such as inulin to increase the growth of the bacteria [paras 000182-000183], thiosulfate that would potentiate the effect of the Lactobacillus [para 000187], and carbon sources for the microbiota such as sodium alginate [para 000210], and one of skill in the art would expect each of these as inferred by Acosta to increase the survival and proliferation of the Lactobacillus in the composition, and thereby increase the effective amount of the Lactobacillus species delivered.
Regarding instant claim 16 and the use of folic acid, folate or a pharmaceutically acceptable salt thereof as the nutritional supplement, Acosta discloses the use of folate salts to maintain low pH [para 000173].
Livengood reviews bacterial vaginosis [title], and discloses the essential manifestations of bacterial vaginosis are well established as the loss of the normal bacterial population of the vagina and their replacement by other species [abstract], therein describing dysbiosis.
Regarding instant claim 16, Livengood discloses “the classic symptom of BV [bacterial vaginosis] is an odor that is usually described as 'fishy'” [p 30, column 3, para 1], as well as that increased vaginal discharge is a more frequent but less specific symptom of BV [p 30, col 3, para 1]. As the method of Acosta can be used for treatment of dysbiosis associated with bacterial vaginosis, and a vaginal odor and increased vaginal discharge are symptoms of bacterial vaginosis, the method of Acosta of treating dysbiosis associated with BV is considered to encompass the treatment of symptoms associated with BV such as vaginal odor, as disclosed by Livengood.
Longoni describes compositions of probiotics, prebiotics, mineral salts and lactoferrin for the effective colonization of probiotic administration [abstract]. These compositions are disclosed to have anti-inflammatory effects, and can be used for the preparation of nutritional supplements and pharmaceutical-grade products.
Regarding instant claim 16 and the limitations regarding lactoferrin, Longoni notes the challenges in administering probiotics, that “to be effective, said probiotics must not only survive manufacturing processing, packaging and storage conditions, but also then must survive transit through the gastrointestinal tract so the probiotic material remains viable to have a positive health effect” [p 3, lines 1-3]. Longoni therefore discloses as a solution to this problem that “compositions comprising a probiotic … and a carrier material comprising prebiotic materials, mineral salts, and lactoferrin will not only have improved and/or enhanced survival of the probiotic species, but also performs the effective colonization of the probiotic components administered with enteric consequences of common dysbioses of the digestive tract caused by stress, incorrect dietary habits, antibiotic treatments, illness and the like” [p 2, line 4-9]. As Longoni discloses the inclusion of lactoferrin to enhance survival of probiotic species for successful colonization and implied treatment of dysbiosis, one of skill in the art would be motivated to include lactoferrin with the Lactobaciillus species for the treatment of dysbiosis disclosed by Acosta above, and would therefore be expected to include the lactoferrin in with the probiotic formulation of the Acosta.
In view of Acosta, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the claims of the patent by replacing the insulin with probiotics, as disclosed by Acosta, since the simple substitution of one known element for another results in a predictable result. One of ordinary skill in the art would have recognized that the probiotics of Acosta and the insulin of the patent are both formulated in a pill, and as such both are capable of being incorporated into an OMCF as described by the patent. Thus it would have been obvious to one of ordinary skill in the art to replace the insulin of the patent with the probiotics of Acosta, as one of ordinary skill in the art would have been able to carry out such a substitution with a reasonable expectation of success because the patent and Acosta are drawn to oral formulations for the delivery of therapeutics.
In view of Acosta, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined OMCF of the patent and Acosta by using the folate of Acosta as the nutrient supplement in the OMCF, since the simple substitution of one known element for another results in a predictable result. One of ordinary skill in the art would have recognized that the folate of Acosta and the nutrient supplement of the patent are both nutrient supplements, and as such both are capable of being incorporated into an OMCF as described by the patent. Thus it would have been obvious to one of ordinary skill in the art to use the folate of Acosta as the nutrient supplement of the patent, as one of ordinary skill in the art would have been able to carry out such a substitution with a reasonable expectation of success because the patent and Acosta are drawn to oral formulations for the delivery of therapeutics.
In view of Longoni, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined OMCF of the patent and Acosta by including lactoferrin with probiotic of Acosta to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to modify the combined OMCF of the patent and Acosta to include lactoferrin because Longoni discloses the use of lactoferrin improves and/or enhances survival of the probiotic species as well as the effective colonization of the probiotic components administered. One of ordinary skill in the art would have had a reasonable expectation of success, because the patent, Acosta and Longoni all discuss therapeutic formulation compositions to increase the longevity of the therapeutic agent.
In view of Livengood and Acosta, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to use the combined OMCF of the patent, Acosta and Longoni to treat vaginal odor, as disclosed by Acosta and Livengood, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to use the combined OMCF of the patent, Acosta and Longoni to treat vaginal odor, because Acosta discloses a method of treating vaginal dysbiosis, and Livengood discloses vaginal odor is a symptom attributed to BV that arises from vaginal dysbiosis. One of ordinary skill in the art would have had a reasonable expectation of success because the patent and Acosta relate to oral formulations for delivery of therapeutics, and Acosta and Longoni relate to the use of oral formulations to treat symptoms of vaginal dysbiosis that include vaginal odor.
Regarding instant claim 18, Acosta discloses “a method of treating dysbiosis in the female genitourinary tract of a human subject”, wherein “dysbiosis can be associated with an infection”, and “the infection can be … vaginal candidiasis” [para 00069].
Regarding instant claim 19, Acosta discloses a “substantially complete vaginal microbiota preparation comprises further lactobacilli other than Lactobacillus crispatus, Lactobacillus iners, Lactobacillus jensenii, or Lactobacillus gasseri, wherein the further Lactobacillus species include, e.g., Lactobacillus acidophilus, Limosilactobacillus fermentum (formerly known as Lactobacillus fermentum), Lacticaseibacillus casei (formerly known as Lactobacillus casei), and Lacticaseibacillus rhamnosus (formerly known as Lactobacillus rhamnosus). As used herein, Limosilactobacillus fermentum, Lacticaseibacillus casei, Lacticaseibacillus rhamnosus are referred to as Lactobacillus and are included in the meaning of Lactobacillus” [para 000116], wherein the formulation comprises at least two species of Lactobacillus, and include further lactobacilli such as Lactobacillus acidophilus and Lactobacillus rhamnosus.
Regarding instant claim 23, the limitations of the instant claim share considerable overlap with the limitations of instant claim 16, with the exceptions that (1) the instant claim does not recite the oral multi-component formulation and its associated architecture recited in instant claim 16, and (2) the instant claim recites specific Lactobacillus species to be included in the instant method. In view of these similarities, the combined method of the patent, Acosta, Livengood, and Longoni as described above is considered to correspond to a method of treating, preventing or ameliorating vaginal odor comprising identifying a subject in need thereof, administering an oral formulation to prevent said vaginal odor, wherein the oral formulation comprises at least two Lactobacillus species, lactoferrin and folic acid, folate or a pharmaceutically acceptable salt thereof as described in the rejection of instant claim 16 above, wherein the formulation comprises at least two species of Lactobacillus that include Lactobacillus acidophilus and Lactobacillus rhamnosus [para 000116 of Acosta]. As the oral formulation is recited to comprise an amount of L. acidophilus and an amount of L. rhamnosus, the claimed combination is interpreted to include other unnamed components, and therefore the combined disclosures of the claims of the patent, Acosta, Livengood, and Longoni are considered to correspond to the limitations in the instant claim.
Claim 24 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 8,586,061 in view of Acosta, Livengood, and Longoni as applied to claims 16, 18-19 and 23 above, and further in view of Ya.
The instant rejection is necessitated by claim amendment.
The claims of the patent and relevant disclosures of Acosta, Livengood, and Longoni as applied to claims 16, 18-19 and 23 are discussed above. The claims of the patent do not recite the amount of L. acidophilus and the amount of L. rhamnosus are present in a ratio of 4:1.
Ya relates to the efficacy of vaginal probiotic capsules for recurrent vaginosis [title], and discusses the standard cure for BV is metronidazole or clindamycin, which have low success rates and high recurrence rates as well as reduce the metabolic activity of vaginal bacteria, and therefore the need to explore new BV therapies exists wherein Lactobacilli present an alternative option for BV prevention [p e1, col 2, paras 2-3].
Regarding instant claim 24, Ya discloses the administration of probiotic capsules containing 6.8 x 109 CFU L. rhamnosus and 0.4 x 109 CFU L. acidophilus to healthy women between 18-55 years old with a history of >2 BV episodes the previous year and had no antibiotic treatment within the 1 week of the study [p e2, col 1, para 3 to col 2, para 1], wherein the probiotic treatment resulted in a reduction of malodor throughout the trial period within the test group and compared to the control [Table 2]. While Ya does not disclose the ratio of 4:1 L. acidophilus to L. rhamnosus as recited in the instant claim, MPEP 2144.05.II.A states where 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. Ya additionally suggests the success of the probiotic is attributed to the dosage of Lactobacillus used which likely overwhelmed the vaginal microbiota to inhibit or destroy pathogenic bacteria causing said symptoms [p e5, col 1, para 2], thereby suggesting Lactobacillus dosage as a result effective variable, which is a variable that achieves a recognized result according to MPEP 2144.05.II.B, which effects the outcome of reducing the symptom of malodor.
In view of Ya, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined method of the patent, Acosta, Livengood, and Longoni by altering the ratio of L. acidophilus and L. rhamnosus, to achieve the claimed ratio of bacterial species, as Ya establishes the general conditions of the administration of 6.8 x 109 CFU L. rhamnosus and 0.4 x 109 CFU L. acidophilus to reduce vaginal odor in patients, and suggests the result effective variable of Lactobacillus dosage as responsible for the observed reduction in vaginal odor. One of ordinary skill in the art would have had a reasonable expectation of success, because Acosta and Ya disclose methods of treating symptoms related to vaginal dysbiosis using formulations comprising L. acidophilus and L. rhamnosus.
Response to Remarks: beginning page 6 of Applicant’s response to double patenting rejections; Applicant in summary contends the claims are not obvious over the ‘061 Patent to Komoroski for the same reasons recited in the response to rejections under 35 USC 103.
Applicant’s remarks are considered and found not convincing. As Applicant’s remarks refer to the rebuttal of rejections under 35 USC 103, the responses to said remarks are the same as above, and are repeated here.
Regarding the argument of “an unexpected advantage” of the formulation in Example 1 over the closest prior art (recited in point (a) on page 3 of Applicant’s remarks), MPEP 2145.II states the recognition of latent properties in the prior art does not render nonobvious an otherwise known invention, and the recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.
Applicant’s assertion that Example 1 of the specification exhibits an unexpected advantage and/or higher efficacy over the prior art is being considered an allegation of unexpected results.
Regarding the allegation that Example 1 of the specification exhibits an unexpected advantage over the prior art, Applicant contends the formulation of the prior art resulted in no statistical difference in the reduction of vaginal odor compared to placebo citing Figure 2, whereas the formulation of Example 1 resulted in significant reductions in vaginal odor at weeks 2, 4, 6, 8, 10 and 12 (p<0.001) [paras 0047-0049 of the instant specification]. As the significance reported in the prior art is derived from a comparison of treatment vs. placebo groups at each timepoint (see Fig. 2 legend), and the significance disclosed in the specification is derived from comparison of symptoms at timepoints compared to symptoms at the onset of the study, the results of the statistical analyses between Example 1 and the prior art are not directly comparable. Put another way, the significance determinations by each study were based both on different criteria and different data, and therefore the lack of significance in one study and the presence of significance in another study are not directly comparable. Example 1 of the instant specification shows a significant reduction in vaginal odor among evaluated study participants compared to their initial evaluated vaginal odor at the onset of the study, but there is no comparison to a placebo group at each timepoint. The study of the prior art shows no significant reduction in vaginal odor at the final timepoint of the treatment group compared to the placebo group at the same timepoint, but there is no statistical evaluation of the change in vaginal odor of study participants compared to their initial evaluated vaginal odor at the onset of the study. According to MPEP 716.02(b).I, the burden is on Applicant to establish results are unexpected and significant, and the evidence relied upon should establish that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance. Therefore, while Example 1 of the specification indeed shows a significant reduction in vaginal odor over time, the allegations that this result is significant over the prior art is not convincing, as the significance determinations between the studies are not directly comparable, and the prior art cited by Applicant still indicates a reduction in vaginal odor over time from participants taking the probiotic supplement. As such, Applicant has not established the results are both unexpected and significant, and the data proffered by Applicant does not establish the differences in results are in fact unexpected and unobvious and of both statistical and practical significance. Therefore Applicant’s allegations of unexpected results do not satisfy the requirements of MPEP 716.02(b).I.
Regarding the assertion that amended claim 16 is commensurate in scope with the formulation of Example 1 in the specification, this assertion is being considered an allegation of unexpected results to rebut the rejection of claims 16 and 18-19 for the reasons set forth above regarding Example 1 compared with the closest prior art. According to MPEP 716.02(d), unexpected results must be commensurate in scope with the claimed invention. As the formulation of Example 1 in the specification from which the alleged unexpected results are derived comprises Lactobacillus acidophilus, Lactobacillus rhamnosus, 400 mcg folate, and 50 mg lactoferrin, the unexpected results are not considered commensurate in scope with the invention of claim 16 that is drawn (in relevant part) to a method of treating, preventing or ameliorating vaginal odor comprising administering a formulation comprising at least two Lactobacillus species, an amount of lactoferrin, and an amount of folic acid, folate, or a pharmaceutically acceptable salt thereof. Put another way, the scope of claim 16 corresponds to the administration of a formulation comprising at least any two of all Lactobacillus species, any amount of lactoferrin, and any amount of folate, whereas the scope of the formulation Example 1 of the specification corresponds to only two Lactobacillus species and single dose each of lactoferrin and folate. Therefore Applicant’s allegations of unexpected results do not satisfy the requirements of MPEP 716.02(d).
Regarding the assertion that new claims 23-24 recite the oral formulation identical or equivalent to Example 1 in the specification which exhibits unexpected higher efficacy than the closest prior art: as discussed above and repeated here, MPEP 716.02(b).I states the burden is on Applicant to establish results are unexpected and significant, and the evidence relied upon should establish that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance. Therefore, while Example 1 of the specification indeed shows a significant reduction in vaginal odor over time, the allegations that this result is significant over the prior art is not convincing, as the significance determinations between the studies are not directly comparable, and the prior art cited by Applicant still indicates a reduction in vaginal odor over time from participants taking the probiotic supplement. As such, Applicant has not established the results are both unexpected and significant, and the data proffered by Applicant does not establish the differences in results are in fact unexpected and unobvious and of both statistical and practical significance. Therefore Applicant’s allegations of unexpected results do not satisfy the requirements of MPEP 716.02(b).I.
Therefore, the applicant's remarks and allegations of unexpected results having been fully considered are not found persuasive to rebut the double patenting rejections of record.
Conclusion
Status of the claims:
Claims 1-10, 16-19 and 23-24 are pending.
Claims 1-10 and 17 are withdrawn from consideration.
Claims 16, 18-19 and 23-24 are rejected.
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/JOSEPH R SPANGLER/
Examiner
Art Unit 1656
/David Steadman/Primary Examiner, Art Unit 1656