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 .
2nd NON-FINAL DETAILED ACTION
1. Applicant’s response filed on March 11, 2026 is acknowledged. Claim 1 has been amended. Claims 16-19 have been added. Claims 1-19 are currently pending and under examination.
Information Disclosure Statement
2. The information disclosure statement (IDS) submitted on March 11, 2026 and January 27, 2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner. An initialed copy is attached hereto.
Rejections Withdrawn
3. In view of Applicant’s amendment, the rejection of claim(s) 1-3, 6-8, and 12-15 under 35 U.S.C. 102(a)(1) as being anticipated by Martinez et al., WO 2019/227085 A1; Published: 11/28/19 is withdrawn.
4. In view of Applicant’s amendment, the rejection of claim(s) 5 and 10 under 35 U.S.C. 103 as being unpatentable over Martinez et al., WO 2019/227085 A1; Published: 11/28/19 as applied to claims 1-3, 6-8, and 12-15 above, and as evidenced by Chromium Fact sheet for health professionals, National Institutes of Health Office of Dietary Supplements; October 2020 is withdrawn.
5. In view of Applicant’s amendment, the rejection of claim(s) 1 and 9 under 35 U.S.C. 103 as being unpatentable over Martinez et al., WO 2019/227085 A1; Published: 11/28/19 as applied to claims 1-3, 6-8, and 12-15 above, and further in view of Ghosal et al., 2019; The Side Effects of Metformin-A Review; Journal of Diabetes & Metabolic Disorders; 6:030 is withdrawn.
Rejections Maintained
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
6. The rejection of claims 1-15 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of reducing insulin resistance in a subject comprising administering an insulin-sensitizing agent selected from the group consisting of chromium, inositol, metformin, sorbitol and is combined with a butyrate-producing bacterium selected from Anaerobutyricum soehngenii (SEQ ID NO: 1 or 2), Intestinimonas butyriciproducens (SEQ ID NO: 3), and Anaerostipes rhamnosivorans (SEQ ID NO: 4), does not reasonably provide enablement for a method of preventing insulin resistance and preventing and treating any and all insulin resistance-related conditions in a subject comprising administering any one of chromium, inositol, metformin, and sorbitol, combined with a butyrate-producing bacterium selected from the group consisting of
Anaerobutyricum soehngenii or relative thereof having a 16S rRNA gene sequence with at least 97% sequence identity with SEQ ID NO: 1 or SEQ ID NO:2;
Intestinimonas butyriciproducens or relative thereof having a 16S rRNA gene sequence with at least 99% sequence identity with SEQ ID NO:3; and
Anaerostipes rhamnosivorans or relative thereof having a 16S rRNA gene sequence with at least 97% sequence identity with SEQ ID NO:4, and combinations thereof is maintained for the reasons set forth in the previous Office action.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) states, “The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art.” “The “amount of guidance or direction” refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling” (MPEP 2164.03). The MPEP further states that physiological activity can be considered inherently unpredictable. Thus, Applicant assumes a certain burden in establishing that inventions involving physiological activity are enabled.
Factors to be considered in determining whether a disclosure would require undue experimentation have been reiterated by the Court of Appeals in In re Wands, 8 USPQ2d 1400 at 1404 (CRFC1988). The Wands factors have been considered in the establishment of this scope of enablement rejection. These factors include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art and (8) the breadth of the claims.
All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention: Independent claim 1 is drawn to a method of preventing and/or treating insulin resistance and/or insulin resistance-related conditions in a subject, the method comprising administering to the subject an insulin-sensitizing agent selected from the group consisting of chromium; inositol; metformin; and sorbitol, wherein the insulin-sensitizing agent is combined with a butyrate-producing bacterium selected from the group consisting of
Anaerobutyricum soehngenii or relative thereof having a 16S rRNA gene sequence with at least 97% sequence identity with SEQ ID NO: 1 or SEQ ID NO:2;
Intestinimonas butyriciproducens or relative thereof having a 16S rRNA gene sequence with at least 99% sequence identity with SEQ ID NO:3; and
Anaerostipes rhamnosivorans or relative thereof having a 16S rRNA gene sequence with at least 97% sequence identity with SEQ ID NO:4,
wherein the butyrate-producing bacterium is micro-encapsulated when
the insulin-sensitizing agent is metformin and the butyrate-producing bacterium is Anaerobutyricum soehngenii or a relative thereof having a 16S rRNA gene sequence with at least 97% sequence identity with SEQ ID NO: 1 or SEQ ID NO:2; or
the insulin-sensitizing agent is chromium or inositol and the butyrate-producing bacterium is Intestinimonas butyriciproducens or relative thereof having a 16S rRNA gene sequence with at least 97% sequence identity with SEQ ID NO:3 or Anaerostipes rhamnosivorans or relative thereof having a 16S rRNA gene sequence with at least 97% sequence identity with SEQ ID NO:4.
Breadth of the claims: The claims are broadly drawn and encompass methods of preventing and treating metabolic diseases which include, but are not limited to insulin resistance and insulin resistance-related conditions; type 1 diabetes mellitus, type 2 diabetes mellitus, dyslipidemia, metabolic syndrome, insulin resistance in endocrine disease, Polycystic Ovary Syndrome (PCOS), Nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH). The breadth of the claim comprises administering to the subject an insulin-sensitizing agent selected from chromium, inositol, metformin, and sorbitol, further combined with a butyrate-producing bacterium selected from the group consisting of a Anaerobutyricum soehngenii strain having a 16S rRNA gene sequence with at least 97% sequence identity with SEQ ID NO: 1 or SEQ ID NO:2; a Intestinimonas butyriciproducens strain having a 16S rRNA gene sequence with at least 97% sequence identity with SEQ ID NO:3; and a Anaerostipes rhamnosivorans strain having a 16S rRNA gene sequence with at least 97% sequence identity with SEQ ID NO:4 and combinations thereof,
Direction or guidance presented in the specification: The specification does not provide enablement for the method as drafted. It seems the ability for the method to function is based upon varying factors as evidenced by the specification, which teaches that the insulin-sensitizing agents alone have limited ability to improve insulin sensitivity. However, when combined with the butyrate-producing bacterium, the insulin-sensitizing agents enhance insulin sensitivity through a synergistic action together with the butyrate-producing bacterium. Similarly, the non-butyrate producing strains have modest ability to improve insulin sensitivity, but which is further enhanced through a synergistic action together with insulin-sensitizing agents (Table 1). Even more surprisingly, the combination of A. soehngenii (or A. hallii) with chromium(III) picolinate leads to an even further increased synergistic improvement of insulin sensitivity and the highest insulin-sensitizing effect (see paragraph 229).
This specification further illustrates that at least one butyrate-producing bacterial strain and at least one insulin-sensitizing agent have a synergistic effect in reducing insulin resistance. At the same time, an example of the spec is used to illustrate that the combination of A. soehngenii (or related strains such as A. hallii), together with chromium or alternate forms of chromium may lead to the largest therapeutic effect in terms of decreasing insulin resistance and therefore may be a preferred embodiment of this disclosure for prevention/treatment of metabolic diseases, such as insulin resistance and/or insulin resistance-related conditions. The claims are not limited to this combination.
The disclosure provides an unexpected, synergistic effect with respect to reducing insulin resistance. In particular, the supplementation of a subject with A. soehngenii and chromium provides a surprisingly large synergistic effect. Such a synergistic interaction between insulin-sensitizing agents and butyrate-producing bacteria has not been reported to date. While, the co-administration of an insulin-sensitizing agent and a butyrate-producing bacterium is believed to be an efficient, the spec has not enabled the breadth of the claims. Particularly as it pertains to of preventing and/or treating metabolic diseases, such as insulin resistance and insulin resistance-related conditions, preferably chosen from type 1 diabetes mellitus , type 2 diabetes mellitus, dyslipidemia, metabolic syndrome, insulin resistance in endocrine disease, Polycystic Ovary Syndrome (PCOS), Nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH). Also, as it pertains to microorganism with 97% sequence identity.
The specification is enabling for a method of reducing insulin resistance; however, the specification has not enabled the treatment or prevention of all that is claimed. Applicant is reminded that to be a prophylactic method and/or composition, said method must induce a protective immune response demonstrated by challenge experiments in an acceptable animal model. The specification does not provide substantive evidence that the claimed composition is capable of inducing protective immunity. This demonstration is required for the skilled artisan to be able to use the claimed method for their intended purpose of prevention. Without this demonstration, the skilled artisan would not be able to reasonably predict the outcome of the administration of the claimed composition, i.e. would not be able to accurately predict if protective immunity has been induced.
Presence or absence of working examples: There are no working examples provided to rectify the missing information in the instant specification pertaining to the claimed methods and the compositions having the ability to have the claimed efficacy.
State of the Prior Art: Insulin resistance is a complex condition in which your body doesn’t respond as it should to insulin. The condition is also associated with:
Obesity
Cardiovascular disease
Metabolic dysfunction-associated steatotic liver disease
Metabolic syndrome
Polycystic ovary syndrome (PCOS)
Not all factors that contribute to the condition can be treated, such as genetic factors and age. For this reason, lifestyle modifications are the primary treatment for insulin resistance. Certain genetic and lifestyle risk factors make it more likely that you’ll develop insulin resistance or prediabetes. You can’t change certain risk factors for insulin resistance, such as family history or age. But you can try lowering your chances of developing it by maintaining a healthy weight for you and exercising regularly (see Insulin Resistance, Cleveland Clinic; https://my.clevelandclinic.org/health/diseases/22206-insulin-resistance; 2024).
Additionally, one can’t change all the factors that contribute to metabolic syndrome, like your genetics and age. But the lifestyle changes that can help treat metabolic syndrome are the same steps that can help prevent it. If you have a family history of diabetes, high blood pressure or high cholesterol, be sure to tell your healthcare provider. It’s also important to schedule routine provider visits. Your provider can keep track of your cholesterol, triglyceride, blood pressure and blood sugar levels. The sooner they can catch any issues, the sooner they can recommend lifestyle changes and treatments to reduce your risk (see Metabolic Syndrome; https://my.clevelandclinic.org/health/diseases/10783-metabolic-syndrome#prevention; 2023.
Lastly, Polycystic ovary syndrome (PCOS) is a common condition that affects your hormones. People with PCOS may be at higher risk for certain health conditions, like diabetes and high blood pressure. Cleveland Clinic teaches that there’s no proven way to prevent PCOS, but you can take small steps to reduce your symptoms. For example, eating nutritious foods, exercising regularly and managing a healthy weight for your body can help you avoid the effects of PCOS (see PCOS, https://my.clevelandclinic.org/health/diseases/8316-polycystic-ovary-syndrome-pcos#prevention; 2023).
Quantity of experimentation necessary predictability in the art: The quantity of experimentation necessary would be undue as the claims encompass a composition capable of preventing tumors. With specific reference to cancer, Ex parte Kranz, 19 USPQ2d 1216, 1219 notes the “general unpredictability of the field [of] …anti-cancer treatment.” In re Application of Hozumi et al., 226 USPQ 353 notes the “fact that the art of cancer chemotherapy is highly unpredictable”. More generally, the invention is directed toward medicine and is therefore physiological in nature. It is well established that “the scope of enablement varies inversely with the degree of unpredictability of the factors involved,” and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). Given the fact that, historically, the development of new cancers drugs has been difficult and time consuming the quantity of experimentation needed is expected to be great.
Reasonable correlation must exist between the scope of the claims and scope of enablement set forth, and it cannot be predicted from the disclosure how to make/use the claimed genus. In view of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention. Thus, for all these reasons, the specification is not considered to be enabling for one skilled in the art to make and use the claimed invention as the amount of experimentation required is undue, due to the broad scope of the claims, the lack of guidance and working examples provided in the specification and the high degree of unpredictability as evidence by the state of the prior art, attempting the construct and test variants of the claimed invention would constitute undue experimentation.
Applicant argues that:
1) Once the specification teaches how to improve insulin sensitivity and reduce insulin resistance, a person of ordinary skill in the art would understand how to apply the disclosed method to disease states that arise from that shared pathophysiological mechanism.
2) The specification provides adequate structural guidance for the claimed bacterial component. 16S rDNA sequence relatedness is well-established microbial classification tool. The specification provides concrete reference sequences, specific names species, and explicitly identity thresholds. The claims do not rely on open-ended functional language alone.
Applicant’s arguments have been fully considered, but are deemed non-persuasive.
With regard to Point 1, the specification is enabling for a method of reducing insulin resistance in a subject comprising administering an insulin-sensitizing agent selected from the group consisting of chromium, inositol, metformin, sorbitol and is combined with a butyrate-producing bacterium selected from Anaerobutyricum soehngenii (SEQ ID NO: 1 or 2), Intestinimonas butyriciproducens (SEQ ID NO: 3), and Anaerostipes rhamnosivorans (SEQ ID NO: 4). A showing of how to improve insulin sensitivity and reduce insulin resistance, would not necessarily apply to the asserted conclusion. The ability for the method to function is based upon varying factors as evidenced by the specification, which teaches that the insulin-sensitizing agents alone have limited ability to improve insulin sensitivity. However, when combined with the butyrate-producing bacterium, the insulin-sensitizing agents enhance insulin sensitivity through a synergistic action together with the butyrate-producing bacterium. Similarly, the non-butyrate producing strains have modest ability to improve insulin sensitivity, but which is further enhanced through a synergistic action together with insulin-sensitizing agents (Table 1). Even more surprisingly, the combination of A. soehngenii (or A. hallii) with chromium(III) picolinate leads to an even further increased synergistic improvement of insulin sensitivity and the highest insulin-sensitizing effect (see paragraph 229).
This specification further illustrates that at least one butyrate-producing bacterial strain and at least one insulin-sensitizing agent have a synergistic effect in reducing insulin resistance. At the same time, an example of the spec is used to illustrate that the combination of A. soehngenii (or related strains such as A. hallii), together with chromium or alternate forms of chromium may lead to the largest therapeutic effect in terms of decreasing insulin resistance and therefore may be a preferred embodiment of this disclosure for prevention/treatment of metabolic diseases, such as insulin resistance and/or insulin resistance-related conditions. The claims are not limited to this combination.
Further, the stated prior art supports the notion that prevention is not an absolute result. Thus, when the state of art teaches that one can’t change all the factors that contribute to metabolic syndrome, like your genetics and age while continuing to note that the same lifestyle changes can help treat metabolic syndrome are the steps that can help prevent it, it makes it necessary to see evidence of prevention in order to patent it. It is known in the art that the sooner doctors can can catch any issues, the sooner they can recommend lifestyle changes and treatments to reduce your risk, implying that there is not sure way to prevent insulin resistance and insulin resistance-related conditions in a subject. Lastly, Cleveland Clinic teaches that there’s no proven way to prevent PCOS, which is a condition falling under the ”insulin resistance related conditions”.
Applicant is encouraged to amend the claim to remove “preventing” and to incorporate the limitations of claim 3.
As it pertains to Point 2, the specification enables a method of reducing insulin resistance in a subject comprising administering an insulin-sensitizing agent selected from the group consisting of chromium, inositol, metformin, sorbitol and is combined with the full-length butyrate-producing bacterium selected from Anaerobutyricum soehngenii (SEQ ID NO: 1 or 2), Intestinimonas butyriciproducens (SEQ ID NO: 3), and Anaerostipes rhamnosivorans (SEQ ID NO: 4). As noted previously, the specification does not reasonably provide enablement for a method of preventing insulin resistance and preventing and treating any and all insulin resistance-related conditions comprising administering any one of chromium, inositol, metformin, and sorbitol, combined with a butyrate-producing bacterium Anaerobutyricum soehngenii or relative thereof having a 16S rRNA gene sequence with at least 97% sequence identity with SEQ ID NO: 1 or SEQ ID NO:2; Intestinimonas butyriciproducens or relative thereof having a 16S rRNA gene sequence with at least 99% sequence identity with SEQ ID NO:3; and
Anaerostipes rhamnosivorans or relative thereof having a 16S rRNA gene sequence with at least 97% sequence identity with SEQ ID NO:4, and combinations thereof. If the claimed invention were drawn to a composition with no specific function, the identity threshold would be less of an issue.
New Grounds of Objection and Rejection Necessitated by Amendment
Claim Objections
7. Claim 1 is objected to because of the following informalities: Applicant amended said claim to recite “99% sequence identity with SEQ ID NO: 3” on its first recitation, however, in the presumed wherein section, it reverts back to “97% sequence identity with SEQ ID NO: 3” . Appropriate correction is required.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
8. Claim(s) 1-3, 6-8, 11, 12-15 are rejected under 35 U.S.C. 102(a)(1)/102(a)(2) as being anticipated by Cutcliffe et al., US 9,486,487 B2; Published: 11/8/16.
Independent claim 1 is drawn to a method of preventing and/or treating insulin resistance and/or insulin resistance-related conditions in a subject, the method comprising administering to the subject an insulin-sensitizing agent selected from the group consisting of chromium; inositol; metformin; and sorbitol, wherein the insulin-sensitizing agent is combined with a butyrate-producing bacterium selected from the group consisting of
Anaerobutyricum soehngenii or relative thereof having a 16S rRNA gene sequence with at least 97% sequence identity with SEQ ID NO: 1 or SEQ ID NO:2;
Intestinimonas butyriciproducens or relative thereof having a 16S rRNA gene sequence with at least 99% sequence identity with SEQ ID NO:3; and
Anaerostipes rhamnosivorans or relative thereof having a 16S rRNA gene sequence with at least 97% sequence identity with SEQ ID NO:4,
wherein the butyrate-producing bacterium is micro-encapsulated when
the insulin-sensitizing agent is metformin and the butyrate-producing bacterium is Anaerobutyricum soehngenii or a relative thereof having a 16S rRNA gene sequence with at least 97% sequence identity with SEQ ID NO: 1 or SEQ ID NO:2; or
the insulin-sensitizing agent is chromium or inositol and the butyrate-producing bacterium is Intestinimonas butyriciproducens or relative thereof having a 16S rRNA gene sequence with at least 97% sequence identity with SEQ ID NO:3 or Anaerostipes rhamnosivorans or relative thereof having a 16S rRNA gene sequence with at least 97% sequence identity with SEQ ID NO:4.
Cutcliffe et al., disclose methods for treating a metabolic disorder in a subject in need thereof comprising administering a therapeutically effective amount of a composition comprising microbes with at least about 85% sequence identity to a rRNA sequence of Eubacterium halli (which has been reclassified as Anaerobutyricum soehngenii) and a pharmaceutically acceptable carrier (see column 1, lines 48-52; column 2, lines 1-7, column 35; lines 53-65; column 39, lines 35-41 (and column 40, line 9); meeting claim 1, 13). Moreover, Cutcliffe discloses that the metabolic condition can be, for example, T2DM or T1DM (see column 37, lines 9-11; meets claim 3). The composition can include one or more active ingredients such as comprises myoinositol at 20 mg/ml (see table 2, meets claim 11-12). Said composition can be formulated as a dietary supplement, such as food and drinks, formulas and yogurts. The composition may also be lyophilized, an enteric-coated capsule, or encapsulated within a suitable vehicle. A therapeutic or cosmetic composition can be encapsulated within a suitable vehicle, for example, a liposome, a microspheres, or a microparticle (see column 49, lines 14-23 and 50-56; column 52, lines 44-63; meets claim 2, 3, 8, 14-15).
Further, Cutcliffe discloses that the composition containing microbes can be administered for prophylactic and/or therapeutic treatments. The agents with can be administered in any order or simultaneously (see column 54, lines 25-60; meets claim 6). The microbe can be from about 101 to about 1018 and in certain embodiments, at most 104 and at most 1015 (see column 55, lines 35-52; meets claim 7).
Finally, Cutcliffe discloses that Anaerobutyricum soehngenii has 16S rRNA gene sequence with 99.9% sequence identity with SEQ ID NO:2 (see SCV results).
PNG
media_image1.png
361
480
media_image1.png
Greyscale
PNG
media_image2.png
620
480
media_image2.png
Greyscale
PNG
media_image3.png
559
491
media_image3.png
Greyscale
PNG
media_image4.png
435
481
media_image4.png
Greyscale
9. Claim(s) 1-3, 6-8 and 12-15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Mulder et al., WO 2021/004958 A2; Published: 1/14/21.
Independent claim 1 is drawn to a method of preventing and/or treating insulin resistance and/or insulin resistance-related conditions in a subject, the method comprising administering to the subject an insulin-sensitizing agent selected from the group consisting of chromium; inositol; metformin; and sorbitol, wherein the insulin-sensitizing agent is combined with a butyrate-producing bacterium selected from the group consisting of
Anaerobutyricum soehngenii or relative thereof having a 16S rRNA gene sequence with at least 97% sequence identity with SEQ ID NO: 1 or SEQ ID NO:2;
Intestinimonas butyriciproducens or relative thereof having a 16S rRNA gene sequence with at least 99% sequence identity with SEQ ID NO:3; and
Anaerostipes rhamnosivorans or relative thereof having a 16S rRNA gene sequence with at least 97% sequence identity with SEQ ID NO:4,
wherein the butyrate-producing bacterium is micro-encapsulated when
the insulin-sensitizing agent is metformin and the butyrate-producing bacterium is Anaerobutyricum soehngenii or a relative thereof having a 16S rRNA gene sequence with at least 97% sequence identity with SEQ ID NO: 1 or SEQ ID NO:2; or
the insulin-sensitizing agent is chromium or inositol and the butyrate-producing bacterium is Intestinimonas butyriciproducens or relative thereof having a 16S rRNA gene sequence with at least 97% sequence identity with SEQ ID NO:3 or Anaerostipes rhamnosivorans or relative thereof having a 16S rRNA gene sequence with at least 97% sequence identity with SEQ ID NO:4.
Mulder discloses methods for the treatment of diabetes and compositions comprising Anaerostipes defined by 16s rRNA gene sequences in an acceptable carrier. The composition may be lyophilized (see page 16, lines 20-31 and page 17, lines 20-22; meets claim 1, 8, 13). Said composition include carriers such a sorbitol (see page 122, lines 29-34; meets claim 1, 12). In some embodiments the composition comprises more than one bacterial strain, species or genus and may be separate, simultaneous, or sequential (see page 127, lines 15-17; meets claim 6). Specifically, Mulder discloses that Anaerostipes rhamnosivorans has a 16S rRNA gene sequence with 100% identity with SEQ ID NO: 4 (see page 35 and attached SCV; meets claim 1).
PNG
media_image5.png
320
535
media_image5.png
Greyscale
PNG
media_image6.png
45
543
media_image6.png
Greyscale
PNG
media_image7.png
737
569
media_image7.png
Greyscale
PNG
media_image8.png
666
562
media_image8.png
Greyscale
PNG
media_image9.png
437
558
media_image9.png
Greyscale
More specifically, the method can be used for treating or preventing diabetes, i.e. type I/II diabetes (see page 99, lines 27-30; meets claim 3). The composition can be encapsuled as a tablet or capsule and administered orally as a food or nutritional product, i.e. milk based product (see page 120-121; meets claim 14-15). The bacteria can be from about 101 to about 1018 and in certain embodiments, at most 104 and at most 1011 CFU (see page 121, lines 9-27; meets claim 7). Pharmaceutical formulations suitable for oral administration include solid microparticulate, semi-solid and liquid such as tablets; soft or hard capsules containing multi- or nano-particulates, liquids (e.g. aqueous solutions), emulsions or powders; lozenges (including liquid-filled); chews; gels; fast dispersing dosage forms; films; ovules; sprays; and buccal/mucoadhesive patches (see page 130, meets claim 2).
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.
10. Claim(s) 1, 4, 5 and 16-19 are rejected under 35 U.S.C. 103 as being unpatentable over Cutcliffe et al., US, 9,486,487 B2; Published: 11/8/16, as applied to claims 1-3, 6-8, 11-15 above, and further in view of Talab et al., Clin Nutr Res., 2020; 9(2):97-106.
Independent claim 1 is drawn to a method of preventing and/or treating insulin resistance and/or insulin resistance-related conditions in a subject, the method comprising administering to the subject an insulin-sensitizing agent selected from the group consisting of chromium; inositol; metformin; and sorbitol, wherein the insulin-sensitizing agent is combined with a butyrate-producing bacterium selected from the group consisting of
Anaerobutyricum soehngenii or relative thereof having a 16S rRNA gene sequence with at least 97% sequence identity with SEQ ID NO: 1 or SEQ ID NO:2;
Intestinimonas butyriciproducens or relative thereof having a 16S rRNA gene sequence with at least 99% sequence identity with SEQ ID NO:3; and
Anaerostipes rhamnosivorans or relative thereof having a 16S rRNA gene sequence with at least 97% sequence identity with SEQ ID NO:4,
wherein the butyrate-producing bacterium is micro-encapsulated when
the insulin-sensitizing agent is metformin and the butyrate-producing bacterium is Anaerobutyricum soehngenii or a relative thereof having a 16S rRNA gene sequence with at least 97% sequence identity with SEQ ID NO: 1 or SEQ ID NO:2; or
the insulin-sensitizing agent is chromium or inositol and the butyrate-producing bacterium is Intestinimonas butyriciproducens or relative thereof having a 16S rRNA gene sequence with at least 97% sequence identity with SEQ ID NO:3 or Anaerostipes rhamnosivorans or relative thereof having a 16S rRNA gene sequence with at least 97% sequence identity with SEQ ID NO:4.
Independent claim 16 is drawn to a method of treating insulin resistance in a subject, the method comprising administering to the subject chromium(III)picolinate in combination with a micro-encapsulated bacterium Anaerobutyricum soehngenii or a relative thereof having a 16S rRNA gene sequence with at least 97% sequence identity with SEQ ID NO: 1 or SEQ ID NO: 2, wherein the bacterium is administered separately, sequentially, or simultaneously with the chromium(III)picolinate.
Cutcliffe teaches methods for treating a metabolic disorder in a subject in need thereof comprising administering a therapeutically effective amount of a composition comprising microbes with at least about 85% sequence identity to a rRNA sequence of Eubacterium halli (which has been reclassified as Anaerobutyricum soehngenii) and a pharmaceutically acceptable carrier (see column 1, lines 48-52; column 2, lines 1-7, column 35; lines 53-65; column 39, lines 35-41 (and column 40, line 9); meeting claim 1, 13). Moreover, Cutcliffe teaches that the metabolic condition can be, for example, T2DM or T1DM (see column 37, lines 9-11; meets claim 3). The composition can include one or more active ingredients such as comprises myoinositol at 20 mg/ml (see table 2, meets claim 11-12). Said composition can be formulated as a dietary supplement, such as food and drinks, formulas and yogurts. The composition may also be lyophilized, an enteric-coated capsule, or encapsulated within a suitable vehicle. A therapeutic or cosmetic composition can be encapsulated within a suitable vehicle, for example, a liposome, a microspheres, or a microparticle (see column 49, lines 14-23 and 50-56; column 52, lines 44-63; meets claim 2, 3, 8, 14-15).
Further, Cutcliffe teaches that the composition containing microbes can be administered for prophylactic and/or therapeutic treatments. The agents with can be administered in any order or simultaneously (see column 54, lines 25-60; meets claim 6). The microbe can be from about 101 to about 1018 and in certain embodiments, at most 104 and at most 1015 (see column 55, lines 35-52; meets claim 7).
Finally, Cutcliffe teaches that Anaerobutyricum soehngenii has 16S rRNA gene sequence with 99.9% sequence identity with SEQ ID NO:2 (see SCV results).
PNG
media_image1.png
361
480
media_image1.png
Greyscale
PNG
media_image2.png
620
480
media_image2.png
Greyscale
PNG
media_image3.png
559
491
media_image3.png
Greyscale
PNG
media_image4.png
435
481
media_image4.png
Greyscale
Cutcliffe does not specifically teach the use of chromium or chromium(III) picolinate, as recited in claim 4 and 5; nor does it specifically teach that their chromium is in an amount ranging from 10 µg to 5000 µg, as recited in claim 10.
Talab teaches a study to evaluate the effects of chromium picolinate (CrPic) supplementation on the glycemic status and lipid profile in patients with T2DM. The subjects were administered 400 µg/day CrPic for eight weeks where T2DM, total cholesterol, LDL-C and insulin resistance decreased significantly. In conclusion the study showed that supplementation of 400 µg CrPic resulted in no improvement in body weight and BMI. However, CrPic could attenuate LDL-C, total cholesterol, and HOMA-IR significantly. It seems that CrPic supplementation might help T2DM patients to improve the disease associated disturbance of lipid profile and insulin resistance.
It would have been obvious before the effective filing date of the presently claimed invention to employ chromium and specifically chromium(III) picolinate as a source of mineral and insulin-sensitizing agent with a reasonable expectation of success. This modification may be viewed as the substitution or addition of particular chromium (chromium picolinate) which were known and suggested in the art to be the most frequently used form; particularly in people with type 2 diabetes to improve the disease associated disturbance of lipid profile and insulin resistance. The skilled artisan would have had a reasonable expectation of success because the substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. See the recent Board decision Ex parte Smith,--USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396).
Furthermore, presenting chromium in an amount ranging from 10 µg to 5000 µg is viewed as a limitation of optimizing experimental parameters. NIH provides intake recommendations for chromium and other nutrients noting that they are provided in the Dietary Reference Intakes (DRIs) developed by an expert committee of the FNB at the National Academies of Sciences, Engineering, and Medicine [2]. DRI is the general term for a set of reference values used for planning and assessing nutrient intakes of healthy people. These values, which vary by age and sex, include the following: Recommended Dietary Allowance, Adequate Intake, Estimated Average Requirement, and Tolerable Upper Intake Level. In a particular trial from 2019, where trials lasted from 3 weeks to 6 months and administered 1.28 to 1,000 mcg chromium daily.
Regarding the specific concentrations listed in the instant claims, MPEP 2144.05 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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997).”
Accordingly, the subject matter of the rejected claims would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the presently claimed invention, absent evidence to the contrary.
11. Claim(s) 1 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Cutcliffe et al., US, 9,486,487 B2; Published: 11/8/16 as applied to claims 1-7 and 11-19 above, and further in view of Ghosal et al., 2019; The Side Effects of Metformin-A Review; Journal of Diabetes & Metabolic Disorders; 6:030.
Independent claim 1 is drawn to a method of preventing and/or treating insulin resistance and/or insulin resistance-related conditions in a subject, the method comprising administering to the subject an insulin-sensitizing agent selected from the group consisting of chromium; inositol; metformin; and sorbitol, wherein the insulin-sensitizing agent is combined with a butyrate-producing bacterium selected from the group consisting of
Anaerobutyricum soehngenii or relative thereof having a 16S rRNA gene sequence with at least 97% sequence identity with SEQ ID NO: 1 or SEQ ID NO:2;
Intestinimonas butyriciproducens or relative thereof having a 16S rRNA gene sequence with at least 99% sequence identity with SEQ ID NO:3; and
Anaerostipes rhamnosivorans or relative thereof having a 16S rRNA gene sequence with at least 97% sequence identity with SEQ ID NO:4,
wherein the butyrate-producing bacterium is micro-encapsulated when
the insulin-sensitizing agent is metformin and the butyrate-producing bacterium is Anaerobutyricum soehngenii or a relative thereof having a 16S rRNA gene sequence with at least 97% sequence identity with SEQ ID NO: 1 or SEQ ID NO:2; or
the insulin-sensitizing agent is chromium or inositol and the butyrate-producing bacterium is Intestinimonas butyriciproducens or relative thereof having a 16S rRNA gene sequence with at least 97% sequence identity with SEQ ID NO:3 or Anaerostipes rhamnosivorans or relative thereof having a 16S rRNA gene sequence with at least 97% sequence identity with SEQ ID NO:4.
Dependent claim 9 is drawn to the method according to claim 1, wherein metformin is present in an amount ranging from 100 mg to 5000 mg.
Cutcliffe teaches the limitations as set forth supra.
Cutcliffe does not specifically teach that their agent is metformin, as recited in claim 1; nor does it specifically teach that metformin is present in an amount ranging from 100 mg to 5000 mg, as recited in claim 10.
Ghosal et al. teach that Type 2 Diabetes mellitus (T2DM) needs to be managed with medications along with a healthy lifestyle to stabilize levels of blood glucose. Metformin is an oral biguanide and a first choice anti-hyperglycemic medication for T2DM. It reduces levels of blood glucose by inhibition of glucose production in the liver. Metformin helps the body to restore its ability to respond to insulin and is generally a safe and effective treatment. Other than glycemic control, metformin also improves insulin resistance, dysfunction of the endothelium, oxidative stress, and haemostasis and lipid profiles.
Moreover, Ghosal teaches that Metformin is available in different formulations such as, tablets, capsules, oral suspensions, oral solutions or modified-release tablets. At the start, the dosage for immediate-release metformin is 500mg two times per day orally or 850mg once per day orally, the maintenance dosage is 2000mg per day in divided doses and the maximum dosage is 2550mg per day. For the extended-release, the initial dosage is 500 to 1000mg orally once a day and the maximum dosage is 2000mg.
It would have been obvious before the effective filing date of the presently claimed invention to employ an agent from an insulin-sensitizing agent as a source of an anti-hyperglycemic medication suggested by Ghosal et al. with a reasonable expectation of success. This modification may be viewed as a combining of known elements in the prior art. The combination of metformin in a patient who is insulin resistance, for instance has T2D, would be obvious because metformin reduces levels of blood glucose by inhibition of glucose production in the liver. Metformin helps the body to restore its ability to respond to insulin and is generally a safe and effective treatment.
All the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art at the time of the invention. See the recent Board decision Ex parte Smith,--USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396).
Lastly, presenting metformin in an amount ranging from 100 mg to 5000 mg would have been obvious before the effective filing date of the presently claimed invention the prior art specifically teaches, that the start, the dosage for immediate-release metformin is 500mg two times per day orally or 850mg once per day orally, the maintenance dosage is 2000mg per day in divided doses and the maximum dosage is 2550mg per day. For the extended-release, the initial dosage is 500 to 1000mg orally once a day and the maximum dosage is 2000mg.
Accordingly, the subject matter of claims 1 and 9 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the presently claimed invention, absent evidence to the contrary.
Conclusion
12. No claims are allowed.
13. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAKIA J JACKSON-TONGUE whose telephone number is (571)272-2921. The examiner can normally be reached Monday-Friday 930AM-530PM.
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, Anne Gussow can be reached at (571) 272-6047. 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.
/LAKIA J JACKSON-TONGUE/Examiner, Art Unit 1645 June 12, 2026
/BRIAN GANGLE/Primary Examiner, Art Unit 1645
Prosecution Insights