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
The amendment filed 10/28/2025 has been entered. Claims 2, 4-25, 26, 29, 30, 33, 36, 37, 41, 43, and 46 are cancelled. Claims 1, 3, 26, 28, 31, 32, 34, 35, 38-40, 42, 44, 45, and 47-51 are pending and under examination.
Response to Arguments
Applicant's arguments filed 10/28/2025 have been fully considered but they are not persuasive. With respect to the rejection of claim 51 under 35 USC 112(b), Applicant argues that the claim is definite because nothing in the claim suggests that steps (b) and (c) are to be operated in isolation. The Examiner respectfully disagrees. The step of freezing the bacterial population is clearly separate from the step of reducing pressure and increasing temperature, as steps (b) and (c) refer to the frozen bacterial population, which is formed in step (a). Therefore, the claim in written in a way that one of ordinary skill in the art would question whether steps (b) and (c) are to be performed separately, or simultaneously.
With respect to the rejection of claims 1, 3, 26, 28, 31, 32, 34, 35, 38-40, 42, 44, 45, and 47-51 under 35 USC 103, Applicant argues that the lyophilization formulation of Azuma at best is used to preserve dead bacteria or bacterial components and that a skilled artisan would not have had any reason to combine the teachings of Cutcliffe and Azuma. Although Azuma uses the formulation for the purpose stated by Applicant, the formulation is still for lyophilization, and there are no teachings in the disclosure of Azuma stating that the presence of urea in the lyophilization formula causes bacterial stress and/or death. Cutcliffe clearly teaches that the viable bacterial populations are lyophilized (para. [019]. Therefore, it would have been obvious to one of ordinary skill in the art to try any known lyophilization formula to preserve the bacterial population of Cutcliffe, including the formula taught by Azuma.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 51 is 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 51 recites: (b) reducing the pressure of the frozen bacterial formulation. Claim 51 also recites: (c) increasing the temperature of the frozen bacterial population, thereby producing the population of lyophilized viable bacteria.
Steps (b) and (c), when operated separately, do not match the method preamble of producing a population of lyophilized viable bacteria. A lyophilizer executes a water removal process typically by freezing the material, then reducing the pressure and adding heat to allow the frozen water in the material to sublimate. Therefore, the action of reducing the pressure and increasing the temperature must occur in the same step simultaneously, not in two separate steps, to achieve lyophilization.
To obviate the rejection, the claim may be amended to recite: (b) reducing the pressure and increasing the temperature of the frozen bacterial formulation, thereby producing the population of lyophilized bacteria.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3, 26, 28, 31, 32, 34, 35, 38, 40, 42, 44, 45, and 47-51 remain rejected under 35 U.S.C. 103 as being unpatentable over Cutcliffe et al., (WO 2018/106844 A1), previously cited, in view of Azuma et al., (US 2008/0152738 A1), previously cited.
Regarding claim 1, Cutcliffe teaches methods for formulating a composition of purified microbes (Abstract). Cutcliffe teaches that the method comprises cultivating the population of isolated and purified microbes in media, and lyophilizing said population (Claim 44). Cutcliffe teaches that the obligate anaerobes are lyophilized with a cryoprotectant (para. [021]).
Cutcliffe does not teach a lyophilization formulation comprising urea.
However, Azuma teaches a lyophilized formulation obtainable by lyophilization of an oil-in-water emulsion comprising a bacterial component, an oil, a surfactant, and a stabilizer (para. [0007]) wherein the stabilizer is urea (para. [0014]). Therefore, is interpreted that the composition of Azuma is considered a lyophilization formulation. Azuma teaches a urea concentration of 2.3% (w/w) (Table 1, Example 1.2). Although the concentration of urea is different from the concentration of the instant invention, MPEP § 2144.05 II states, “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. ‘[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.’” The selection of specific urea concentrations would have been a routine matter of optimization and experimentation on the part of the artisan of ordinary skill, said artisan recognizing that the bacterial viability may be affected by said concentrations.
It would have been obvious to one of ordinary skill in the art, prior to the effective filing date of the claimed invention, to lyophilize the bacterial population of Cutcliffe with 2.3% (w/w) of urea, as taught by Azuma. One of ordinary skill in the art would have been motivated to do so because Azuma teaches that urea is a suitable stabilizer for a lyophilization formulation (para. [0014]). One of ordinary skill in the art would have had a reasonable expectation of success because Cutcliffe and Azuma are in the same field of endeavor of lyophilization methods.
Regarding claim 3, Cutcliffe teaches that the cryoprotectant may be sucrose (para. [021]), which is a sugar. Cutcliffe teaches that the formulation for administration can include carriers or excipients such as salts (para. [0265]), and teaches that the therapeutic composition may be lyophilized (para. [0272]). Therefore, it is interpreted that salt may be part of the lyophilization formulation. Cutcliffe teaches that potassium chloride is a salt (Claim 51). It would have been obvious to one of ordinary skill in the art that the composition to be lyophilized may contain potassium salt, based on the teachings of Cutcliffe.
Azuma teaches that the lyophilization formulation may contain albumin or gelatin (para. [0157]). Azuma teaches that the formulation may contain an antioxidant or a buffering agent, which may be added at any stage (para. [0062]). Although Azuma does not teach specific antioxidants or buffering agents, Cutcliffe teaches the use of ascorbic acid (Claim 54), which is a known antioxidant, and teaches that 4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid (HEPES) is a buffering agent (para. [0120]). It would have been obvious to one of ordinary skill in the art that ascorbic acid and HEPES, as taught by Cutcliffe, may be used as the antioxidant and buffering agent, respectively, in the lyophilization formulation of Azuma.
Regarding claims 26 and 28, as stated, Cutcliffe teaches that the population of isolated and purified microbes comprises obligate anaerobes that are viable or active cells (para. [05]). Cutcliffe also teaches that the term “anaerobe” may include aerotolerant or facultative anaerobes (para. [083]).
Regarding claim 31, Cutcliffe teaches that microbes may be aerobic (para. [068]).
Regarding claim 32, Cutcliffe teaches that the composition comprises a population of one or more isolated and purified microbes comprising one or more obligate anaerobes (Claim 1). It is interpreted that one or more obligate anaerobes may encompass bacteria of different species, i.e., more than one OTU.
Regarding claims 34 and 35, Cutcliffe teaches that the population may contain Clostridium species that can be endospore-forming bacteria (para. [0116]). Cutcliffe teaches that the microbes may be formulated as a population with small amounts of spores (para. [0255]).
Regarding claim 38, Cutcliffe teaches that a composition may comprise one or more populations of microbes, selected from: Akkermansia, Clostridium, Ruminococcus, Bifidobacterium, Streptococcus, or Peptostreptococcus (para. [0109]).
Regarding claim 40, Cutcliffe teaches that the microbial composition may be lyophilized to yield a stable particulate composition (para. [090]). Cutcliffe teaches that the composition may be a powder (para. [0173]).
Regarding claim 42, Cutcliffe teaches that the method of formulating a composition of isolated or purified microbes may further comprise encapsulating said mixture in an enteric-coated capsule for delivery to a subject (Abstract). As stated, Cutcliffe teaches that the composition may be a powder (para. [0173]).
Regarding claim 44, Cutcliffe teaches that the composition of the disclosure may be used to treat a condition or a disorder (para. [0193]). Cutcliffe teaches that the disorder may include Crohn’s disease, colitis, or ulcerative colitis (para. [0196]), which are gastrointestinal disorders.
Regarding claim 45, Cutcliffe teaches the composition may comprise isolated and purified microbes and a pharmaceutically acceptable carrier (Abstract). As stated, Cutcliffe teaches that the composition may be a powder (para. [0173]).
Regarding claims 47 and 48, Cutcliffe teaches that the composition of the disclosure may be used to treat a microbiome-associated health condition (para. [0188]). Cutcliffe teaches that examples of health conditions that can be associated with the microbiome can include inflammatory bowel disease, C. difficile infection, obesity, diabetes, allergies, asthma, or cardiovascular diseases (para. [0190].
Regarding claim 49, as stated, Cutcliffe teaches methods for formulating a composition of purified microbes (Abstract). Cutcliffe teaches that the method comprises cultivating the population of isolated and purified microbes in media, and lyophilizing said population (Claim 44). Cutcliffe teaches that the population of isolated and purified microbes comprises viable or active cells (para. [05]). Cutcliffe teaches that the obligate anaerobes are lyophilized with a cryoprotectant (para. [021]), while, Azuma teaches a lyophilization formulation wherein the stabilizer is urea (para. [0014]) at a concentration of 2.3% (w/w) (Table 1, Example 1.2). Cutcliffe teaches that the composition remains stable when stored at a temperature of 4 degrees Celsius or room temperature for 2 weeks or more (para. [04]). Therefore, it is considered that the combination of Cutcliffe and Azuma teach a method of stabilizing viable bacteria via lyophilization.
Regarding claim 50, Cutcliffe teaches that the method may yield up to 100% viable cells (para. [0152]). As stated, the combination of Cutcliffe and Azuma teach lyophilization with urea. Therefore, it is considered that the method of Cutcliffe and Azuma would inherently increase bacterial yield.
Regarding claim 51, as stated above, the combination of Cutcliffe and Azuma teach the bacterial composition of the instant invention. Cutcliffe teaches that, once grown, the bacterial strains may be lyophilized, also referred to as freeze drying (para. [0145]). Cutcliffe teaches that, after lyophilization buffer is added, the culture may be frozen (para. [0150]), placed in a lyophilizer that may reach a pressure of 75-500 millitorr, at a temperature of at most -10 degrees Celsius (para. [0150]), resulting in a lyophilized product. Therefore, it is considered that the product of Cutcliffe is subjected to reduced pressure.
Claim 39 remains rejected under 35 U.S.C. 103 as being unpatentable over Cutcliffe et al., (WO 2018/106844 A1) in view of Azuma et al., (US 2008/0152738 A1) as applied to claim 1 above, and further in view of Schneider et al. (U.S. Patent No. 9,999641 B2, filed 06/22/2017), previously cited.
As stated above, Cutcliffe teaches the lyophilization of microbial compositions comprising viable bacteria, while Azuma teaches 2.3% (w/w) urea as a lyophilization stabilizer.
Cutcliffe and Azuma do not teach lyophilization of bacteria with the 16S rDNA sequences of instant claim 39.
However, Schneider teaches compositions for the treatment of pathogenic infections including C. difficile wherein the composition comprises two or more purified bacterial strains (Column 2, lines 47-51). Schneider teaches a sequence (SEQ ID NO:98) that is 98.1% identical to SEQ ID NO:2 of the instant disclosure (see alignment attached to this Office action).
It would have been obvious to one of ordinary skill in the art, prior to the effective filing date of the claimed invention, to preserve bacteria with the 16S rDNA sequence taught by Schneider, using the lyophilization methods taught by the combination of Cutcliffe and Azuma. One of ordinary skill in the art would have been motivated to do so because Cutcliffe teaches that organisms in the Clostridia class may be used in the composition while Schneider teaches that SEQ ID NO:98 is from Clostridium innocuum (Column 133 of Schneider). One of ordinary skill in the art would have had a reasonable expectation of success because Cutcliffe, Azuma, and Schneider are in the same field of endeavor of bacterial therapeutic development.
Conclusion
THIS ACTION IS MADE FINAL. 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 RACHEL EMILY MARTIN whose telephone number is (703)756-1416. The examiner can normally be reached M-Th 8:30-16:00, F 8:30-10:00 EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Louise 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.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/RACHEL EMILY MARTIN/Examiner, Art Unit 1657