DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election of Group I (i.e., claims 1-9 drawn to a method of mitigating and or preventing side effects from radiation therapy); and Species A, a single and specific bacterium and/or metabolite (i.e., claims 1-2, 5-6, Lachnospiraceae), and Species B, a single and specific condition the subject is suffering from (i.e., claims 7-8, hematopoietic injury) in the reply filed on February 1st, 2024 are acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
In light of the Examiner’s search, Species A, a single and specific bacterium and/or metabolite (i.e., claims 1, 2, 5-6) is expanded to include a Lachnospiraceae metabolite of Tryptophan; and Species B, a single and specific condition the subject is suffering from (i.e., claims 7-8) is expanded to include the condition gastrointestinal (GI) injury/gastrointestinal syndrome.
Status of Claims
Claims 1-42 were originally filed on June 14th 2021.
The amendment received on January 14th 2022, amended claims 2, 5-9, 13, 16, 18-19, 25-27 and 29-30; and cancelled claims 4, 10-11, 15, 20-21, 28 and 31-42.
The amendment received on August 8th 2024, amended claims 1 and 6-9; and cancelled claims 2-3.
The amendment received on May 19th 2025, amended claims 1 and 8-9; and cancelled claim 5.
The amendment received on December 8th 2025, amended claim 1 and added new claim 43.
Claims 1, 6-9, 12-14, 16-19, 22-27, 29-30 and 43 are currently pending and claims 1, 6-9 and 43 are under consideration as claims 12-14, 16-19, 22-27, 29 and 30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on February 1st 2024.
Priority
The present application claims status as a 371 (National Stage) of PCT/US2019/066606, filed on December 16th 2019 and claims the benefit under 35 U.S.C 119 (e) to U.S. Provisional Application No. 62/779,776, filed on December 14, 2018. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C 119 (e) or under 35 U.S.C 120, 121, or 365 (c) is acknowledged.
Claim Interpretation
For purposes of applying prior art, the claim scope has been interpreted as set forth below per the guidance set forth at MPEP § 2111. If Applicant disputes any interpretation set forth below, Applicant is invited to unambiguously identify any alleged misinterpretations or specialized definitions in the subsequent response to the instant action. Applicant is advised that a specialized definition should be properly supported and specifically identified (see, e.g., MPEP § 2111.01(IV), describing how Applicant may act as their own lexicographer).
For claims 7 and 8, regarding the scope of “hematopoietic (HP) injury” and “hematopoietic syndrome,” and “gastrointestinal (GI) injury” and “gastrointestinal syndrome” it is noted that the instant specification does not define what constitutes “hematopoietic injury/syndrome” nor “gastrointestinal injury/syndrome.” Pursuant to MPEP 2111.01, under a broadest reasonable interpretation, words of the claim must be given their plain meaning, unless such meaning is inconsistent with the specification. The plain meaning of a term means the ordinary and customary meaning given to the term by those of ordinary skill in the art at the time of the invention. According to Wang et al., the hematopoietic system is organized in a hierarchical manner, in which rare hematopoietic stem cells (HSCs) initiate the hierarchy and have the ability to self-renew, proliferate and differentiate into different lineages of peripheral blood cells though inter-mediating hematopoietic progenitor cells (HPCs) (see Wang et al., Cell Cycle, (2006) 5:1, pp. 35-38 at pg. 35, second paragraph). The depletion of HPCs by chemotherapy and/or ionizing radiation (IR) during cancer therapy results in acute myelosuppression (see Wang et al., pg. 35, second paragraph). In this situation, HSCs can undergo self-renewing proliferation and differentiation to repopulate HPCs and to restore homeostasis (see Wang et al., pg. 35, third paragraph). However, if the self-renewal ability of HSCs is impaired, long-term or permanent damage to the hematopoietic system occurs and bone marrow failure and death of the organism may ensue (see Wang et al., pg. 35, third paragraph). If full body irradiation takes places, the bone marrow is irradiated, and this radiation prevents blood cells from being generated effectively (see Nett., Acute Radiation Syndromes [Hematopoietic, GI, CNS] for Radiologic Technologies, in HowRadiationWorks, 2021, at pg. 4 (available online at https://howradiologyworks.com/acute-radiation-syndromes/) accessed on 02/28/2024). The severity of the effects depends on the dose of radiation (see Nett, pg. 4). For doses of radiation, down to as low as 0.7 Gy, we can see effects of bone marrow syndrome (see Nett, pg. 4). Moreover, hematopoietic syndrome involves generalized pancytopenia, which is a deficiency of all three cellular components of the blood: red cells, white cells and platelets (see Cleveland Clinic., Diagnosis and Tests, Radiation Sickness, 2022, at pg. 7, (available online at https://my.clevelandclinic.org/health/diseases/24328-radiation-sickness) accessed on 02/20/2024). The prodromal phase is mild and may begin one to six hours after exposure, lasting 24 to 48 hours (see Cleveland Clinic, pg. 7). The latent asymptomatic phase lasts about four weeks (see Cleveland Clinic, pg. 7). Symptoms of the overt phase include: risk of various infections due to neutropenia and decreased antibody production, petechiae and mucosal bleeding, which may last for months and anemia which develops slowly (see Cleveland Clinic, pg. 7).
Regarding the scope of “gastrointestinal injury,” Nett teaches that there are linings inside of the intestine and crypts (small indentations within the gut) (see Nett., pg. 5). The mucosal membrane covers the inside of the gut including all indentations (see Nett., pg. 5). Similar to bone marrow disease, the issue here is that the mucosal membrane is replenished constantly and after this high level of irradiation the membrane cannot be replenished (see Nett., pg. 5). In such cases, GI syndrome leads to vomiting and diarrhea (see Nett., pg. 5). This becomes fatal, as patients don’t have ability to keep water in the body (see Nett., pg. 5). If you have radiation dose above 10Gy, the GI syndrome will be fatal within 10 days (see Nett., pg. 5). This occurs more quickly than bone marrow syndrome as the cells are replenished more quickly and the symptoms are more severe than bone marrow syndrome (see Nett., pg. 5). Additionally, according to the Cleveland Clinic, symptoms of gastrointestinal (GI) syndrome develop within about one hour after exposure and resolve within two days and the latent phase lasts four to five days (see Cleveland Clinic, pg. 6). Symptoms of the overt systemic illness phase include: severe nausea, vomiting and diarrhea, necrosis (death) of your intestines, which could lead to sepsis (see Cleveland Clinic, pg. 7).
As such, the Examiner is interpreting the scope of “hematopoietic injury” as the impairment of hematopoietic stem cells to self-renew after a radiation dose level of as low as 0.7Gy and “hematopoietic syndrome” as symptoms related to the injury which involve generalized pancytopenia, risk of infection due to neutropenia, decreased antibody production and anemia. Similarly, the scope of “gastrointestinal (GI) injury” is being interpreted as the impairment of the mucosal membrane of the gut to self-renew after a radiation dose level above 10Gy and “gastrointestinal syndrome” as symptoms related to the injury which involve severe nausea, vomiting, diarrhea and even necrosis of the intestines.
Response to Arguments
1. Applicants’ arguments, see Response, filed 12/08/2025, with respect to 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement, have been fully considered but are not persuasive. The 35 U.S.C. 112(a) rejection to claims 1 and 6-9 has been maintained.
2. Applicants’ arguments, filed 12/08/2025, with respect to 35 U.S.C. 103 as being unpatentable over US 2020/0368295 A1 published on Nov. 26, 2020 with PCT filing date of Aug. 7, 2018, (herein after “Santiago”), as evidenced by US 11,395,838 B2, Date of Patent: Jul. 26, 2022, with Provisional Application No. 62/400,372, filed on Sep. 27, 2016 (herein after “Wargo.”) have been fully considered but are not persuasive. The 35 U.S.C. 103 rejection to claims 1 and 6-9 has been maintained.
New Rejection
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.
1. Claim 1 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventors, at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
In the instant case, claim 1 was amended to recite: “ A method of mitigating side effects from radiation therapy, the method comprising: “[…] (iv) selecting one or more Lachnospiraceae strains that produce butyrate at a concentration higher than about 120 µM and propionate at a concentration higher than about 60 µM; and (v) administering to the subject Lachnospiraceae from the one or more Lachnospiraceae strains selected in step (iv) […]”.
Applicants stated in their remarks that “no new matter has been added” (see Remarks, filed 12/08/2025, pg. 7, second paragraph), and that support for the amendments can be found throughout the specification and claims as filed. However, the support (i.e., specification filed on 06/16/2021) provided by Applicants does not support that the amendments to claim 1 were previously presented, as the specification is silent about the instantly claimed method comprising the newly added limitations (i.e., (iv) selecting one or more Lachnospiraceae strains that produce butyrate at a concentration higher than about 120 µM and propionate at a concentration higher than about 60 µM, and (v) administering to the subject Lachnospiraceae from the one or more Lachnospiraceae strains selected in step (iv)).
The specification is void of evidence that would clearly support the instantly claimed method. The specification does not teach a method of mitigating side effects from radiation therapy, wherein the method comprises the newly added claimed limitations recited in (iv) and (v).
Examination of the instant support, in particular of pg. 17, lines 31-33 to pg. 18, lines 1-12, describes “administering to the subject a bacterium and/or metabolite thereof, wherein the bacterium comprises one or more bacterial strains capable of producing short chain fatty acids (SCFAs), wherein side effects from radiation therapy are mitigated and/or prevented in the subject. In some embodiments, the bacterium comprises intestinal microbiota. In some embodiments, the bacterium comprises Lachnospiraceae strains, optionally wherein the Lachnospiraceae strains produce butyrate higher than about 120 μM and propionate higher than about 60 μM.” Therefore, the instantly claimed method comprising selecting one or more Lachnospiraceae strains that produce butyrate at a concentration higher than about 120 µM and propionate at a concentration higher than about 60 µM, is not supported by the evidenced provided, since production of butyrate higher than about 120 µM and propionate higher than about 60 µM by Lachnospiraceae strains is an optional feature of the Lachnospiraceae strains administered as part of the method of mitigating the side effects from radiation therapy.
Similarly, Figs. 6A and 6B only present data of six Lachnospiraceae strains, which have been categorized as Low SCFA producers (i.e., Lachno 8, Lachno 9, Lachno 21) and high SCFA producers (i.e., Lachno 2, Lachno 14, Lachno 20). However from looking at the data depicted in Fig. 6A, any of the six Lachno strains could produce the claimed concentration of butyrate and propionate (i.e., higher than about 120 μM, and higher than about 60 μM). Since the y-axis only depicts major tick marks every 500 units up to 20000 (i.e., at 500µM, 1000µM, 1500µM, 2000µM, etc.); and since the bar graph lacks tick marks indicating intervals below 500µM; it is difficult to confirm whether any of the Lachno Low SCFA producers (i.e., Lachno 8, Lachno 9 and Lachno 21) indeed produce butyrate at a concentration below about 120 µM and propionate at a concentration below about 60 µM.
As such, Fig. 6A clearly depicts that Lachno 2, Lachno 14 and Lachno 20 produce butyrate at a concentration higher than 500µM; while only Lachno 20 produces propionate at a concentration higher than 500 µM. Additionally, the names Lachno 8, Lachno 9, Lachno 21, Lachno 2, Lachno 14, Lachno 20 are not indicative of a specific strain that can be traced to a sequence/structure (i.e., amino acid or nucleotide) that evidences the claimed production of butyrate and propionate higher than about 120µM and higher than 60µM, respectively. It is evident that the instant specification provides support for Lachnospiraceae strains that optionally produce butyrate higher than about 120 μM and propionate higher than about 60 μM. Therefore, evidence of the production of butyrate and propionate above 500µM by any Lachnospiraceae strain, does not provide support in claiming a method of mitigating side effects from radiation therapy, the method comprising: (iv) selecting one or more Lachnospiraceae strains that produce butyrate at a concentration higher than about 120 µM and propionate at a concentration higher than about 60 µM, and (v) administering to the subject Lachnospiraceae from the one or more Lachnospiraceae strains selected in step (iv).
It is ambiguous and/or unclear which of the one or more Lachno strains produce the claimed concentrations of SCFA. In other words, an ordinary skilled artisan would not be able to select with certainty one or more Lachnospiraceae strains that produce butyrate at a concentration higher than about 120 µM and propionate at a concentration higher than about 60 µM, as part of a method of mitigating side effects from radiation therapy, because the specification the specification fails to teach selection of one or more Lachnospiraceae strains that produce butyrate at a concentration higher than about 120 μM and propionate higher than about 60 μM and also fails to teach administering to the subject Lachnospiraceae from one or more Lachnospiraceae strains selected in step (iv).
With respect to “(ii) providing a plurality of Lachnospiraceae strains and growing each of said plurality of Lachnospiraceae strains in a separate culture medium under anaerobic conditions for 7 days” and “(iii) detecting concentrations of butyrate and propionate in culture supernatants from each culture medium from step (ii)”. It is acknowledged that the instant specification teaches that “individual Lachnospiraceae strains were grown anaerobically for 7 days” (see pg. 9, lines 11-12); and that “culture supernatants were then collected and 13C1-butyrate was added to serve as an internal standard for the extraction efficiency of butyrate. Proteins were removed from the supernatant by centrifugation through a 3-kDa spin-filter. Flow through was then analyzed for butyrate, isobutyrate, propionate and lactate content by HPLC separation with subsequent detection by an Agilent 6520 AccurateMass Q-TOF mass spectrometer” (see pg. 9, lines 12-18).
Although pending claims must be given their broadest reasonable interpretation consistent with the specification” see MPEP 2111, and considering that while there is no in haec verba requirement, newly added claims or claim limitations must be supported in the specification through express, implicit, or inherent disclosure (see MPEP 2163 (I) B), there is insufficient written description to support a method of mitigating side effects from radiation therapy, the method comprising: “(ii) providing a plurality of Lachnospiraceae strains and growing each of said plurality of Lachnospiraceae strains in a separate culture medium under anaerobic conditions for 7 days; (iii) detecting concentrations of butyrate and propionate in culture supernatants from each culture medium from step (ii)”. In other words, the newly added claim limitations, although supported by the specification, do not support the claimed method of mitigating side effects from radiation therapy. Instead, the newly added limitations give rise to a completely different method/embodiment which is not supported by the instant specification.
Maintained/Modified Rejection in light of Amendment
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.
2. Claims 1, 6-9 and 43 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventors, at the time the application was filed, had possession of the claimed invention.
MPEP § 2163 states that the written description requirement for a claimed genus may be
satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or
chemical properties, by functional characteristics coupled with a known or disclosed correlation
between function and structure, or by a combination of such identifying characteristics, sufficient to
show the inventor was in possession of the claimed genus.
To satisfy the written-description requirement, the specification must describe every element of
the claimed invention in sufficient detail so that one of ordinary skill in the art would recognize that the
inventor possessed the claimed invention at the time of filing. Vas-Cath, 935 F.3d at 1563; see also
Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572 (Fed. Cir. 1997) (patent specification must
describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that
“the inventor invented the claimed invention’); In re Gosteli, 872 F.2d 1008, 1012 (Fed. Cir. 1989) (“the
description must clearly allow persons of ordinary skill in the art to recognize that [the inventor]
invented what is claimed’).
Independent claim 1 includes (ii) providing a plurality of Lachnospiraceae strains and growing each of said plurality of Lachnospiraceae strains in a separate culture medium under anaerobic conditions for 7 days; […] (iv) selecting one or more Lachnospiraceae strains that produce butyrate at a concentration higher than about 120 µM and propionate at a concentration higher than about 60 µM; and (v) administering to the subject Lachnospiraceae from the one or more Lachnospiraceae strains selected in step (iv); wherein side effects from radiation therapy are mitigated in the subject.
Bacterial strains capable of producing SCFAs are known in the art, for instance Lin et al. teach that in human gut, bacteria of the Bacteroidetes phylum secrete high levels of acetate and propionate whereas those of the Firmicutes phylum generate large amounts of butyrate (see Lin et al., pg. 5, left column, paragraph 1). It is also known that in Firmicutes and Bacteroidetes dominate the gut microbiota in healthy subjects, and that the Lachnospiraceae family is a phylogenetically and morphologically heterogenous taxon belonging to the clostridial cluster XIVa of the phylum Firmicutes (see Vacca et al., Microorganisms 2020, 8, 573, pp. 2-25 at pg. 2, first paragraph). Thus, an ordinary skill artisan would be well aware of what is referred to as “Lachnospiraceae strains that produce butyrate and propionate.”
However, the specification is silent about a specific strain(s) of Lachnospiraceae capable of producing butyrate higher than about 120µM and propionate higher than about 60µM. Therefore, the scope of the claimed method of “mitigating side effects from radiation therapy, the method comprising: “[…] administering to the subject Lachnospiraceae, from the one or more Lachnospiraceae strains selected in step (iv)” in claim 1 implies that any strain(s) of Lachnospiraceae would have the necessary core structure/sequence needed to exhibit the function of producing butyrate higher than 120µM and propionate higher than about 60µM.
Thus the scope of the claimed invention encompasses a large array of strains of Lachnospiraceae without any necessary core structure and/or sequence that would be required to exhibit the instantly claimed function of producing butyrate and propionate higher than the claimed amounts (i.e., 120µM and 60µM, respectively) in order to mitigate the side effects from radiation therapy in a subject.
The written description requirement may be met by provided a representative number of species of the genus and/or in light of the state of the art. With regard to the state of the art, it is known that Lachnospiraceae are currently described in the National Center for Biotechnology Information (NCBI) as comprising 58 genera and several unclassified strains (see Vacca, bottom of pg. 2). With Lachnospiraceae, Blautia, Coprococcus, Dorea, Lachnospira, Oribacterium, Roseburia, and L-Ruminococcus (Ruminococcus genus assigned to the Lachnospiraceae family) being the main genera that have been detected in the human intestine by metagenomics analyses (see Vacca, pg. 3, first paragraph). Vacca also teaches that the major products of microbial fermentation within the human colon are acetate, propionate, and butyrate, with ratios ranging from 60:20:20 to 77:15:8 (see Vacca, pg. 4, second paragraph). Vacca’s Table 1 displays the main metabolic pathways and corresponding Lachnospiraceae taxa involved in the production of compounds that affect human health such as: butyrate, propionate and acetate (see Vacca, Table 1, pg. 6). It is noted only a handful of the Taxa described in Table 1 are capable of producing butyrate and propionate through different pathways. For instance Blautia spp. is able to produce butyrate through the Butyril-CoA: acetate CoA transferase (2.8.3.8), and Blautia obeum A2.162 is able to produce propionate through the Propanediol pathways (4.2.1.28, 1.2.1.87, 2.8.3.1) (see Vacca, pg. 6, Table 1). In other instances, the strains are capable of producing two metabolites, such as Coprococcus catus GD/7, which is capable of producing butyrate through the Butyril-CoA:acetate CoA transferase pathway and acetate through the Acetate kinase (2.7.2.1) pathway (see Vacca, pg. 6, Table 1). However, not all the bacterial strains belonging to the genus Blautia are the same, and not all the same strains (i.e., Coprococcus catus) are capable of producing the three metabolites; and as previously mentioned the Lachnospiraceae family currently comprises 58 genera and several unclassified strains, additionally the strains capable of producing butyrate and propionate depicted in Table 1 (e.g., Blautia and Coprococcus catus) do not support a representative number of the species that exhibit the claimed function.
The specification teaches increases in the abundance of Bacteroidales and Clostridiales orders in mice who survived exposure to a lethal dose of total body irradiation (TBI), with Lachnospiraceae being a more abundant bacterium in the survivors group (see instant specification, pg. 16, lines 6-13). Furthermore, the function of butyrate, which is a commonly studied metabolite that is also produced by Lachnospiraceae, was detected and the Applicants found that this short chain fatty acid had radio mitigation properties albeit less than Lachnospiraceae (see instant specification, pg. 16, lines 17-21). Also, example 5 in the instant specification teaches that administration of Lachnospiraceae effectively attenuated radiation induced hematopoietic and gastrointestinal syndrome (see instant specification, pg. 32-33). Moreover, example 6 teaches that increased abundance of Lachnospiraceae is expected to enhance the capability to produce SCFAs (see instant specification, pg. 33, lines 28-29). The concentrations of lactate, propionate, isobutyrate and butyrate were detected in each individual Lachnospiraceae strain within the disclosed 23 stains pool (see instant specification, pg. 33, lines 30-31). Lachnospiraceae strains which produce butyrate higher than 120 µM and propionate higher than 60µM, are expected to have better outcome in protecting against radiation-induced damage (see instant specification, pg. 34, lines 2-5). Example 10 in the instant specification teaches that SPF C57BL/6 mice were treated with acetate, butyrate or propionate supplemented water for 8 weeks respectively, followed by a lethal dose TBI (see instant specification, pg. 37, lines 20-21). While, acetate and butyrate showed slight protection, elevated bone marrow cellularity and splenic white and red pulp recovery were also observed in the propionate-treated group (see instant specification, pg. 37, lines 24-26). These findings indicate that propionate leads to protection from hematopoietic and gastrointestinal syndromes (see instant specification, pg. 38, lines 3-4). Finally, Example 12 teaches that two other bacteria strains (Enterococcus faecalis and Bacteroides fragilis) were tested, which were increased in elite-survivors detect by 16s rRNA sequencing, together with the well-known probiotics, Lactobacillus rhamonosus. These strains were cultured in vitro and separately transferred into SPF mice for 8 weeks, followed with lethal dose TBI and monitoring of the survival rate and clinical scores (Fig 13A). The data shows Enterococcus faecalis and Lactobacillus rhamonosus both have a radioprotective function with a survival rate around 40%-60% but not as dramatic as Lachnospiraceae (75% survival) see Fig 13B-13C (see instant specification, pg. 38, lines 18-26). There is evidence in the instant specification that more than one bacterium, with different sequences (i.e., Lachnospiraceae, Enterococcus faecalis and Lactobacillus rhamonosus) and more than one metabolite, with different core structures (i.e., acetate, butyrate and propionate) exhibit the claimed function of mitigating side effects from radiation therapy in a subject.
Therefore, the specification demonstrates that any bacterium and/or metabolite thereof encompass a large array of compounds with no necessary core structure to produce the claimed SCFAs in order to mitigate side effects from radiation therapy. Since the instant method of mitigating side effects from radiation therapy comprises administering to the subject Lachnospiraceae from the one or more Lachnospiraceae strains that produce butyrate higher than about 120µM and propionate higher than about 60µM, and since the instant specification fails to teach a sequence/structure associated to the one or more Lachnospiraceae strains responsible for producing the claimed concentration of butyrate and propionate (i.e., higher than about 120µM and higher than about 60µM, respectively); an ordinary skilled artisan would conclude that Applicants are not in possession of the claimed genus.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, what is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
Accordingly, claims 1, 6-9 and 43 do not meet the written description requirement.
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.
103 - KSR Examples of 'Rationales' Supporting a Conclusion of Obviousness
(Consistent with the "Functional Approach" of Graham)
Further regarding 35 USC 103(a) rejections, the Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 127 S. Ct. 1727, 82 USPQ2d 1385, 1395-97 (2007) (KSR) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit.
Exemplary rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Note that the list of rationales provided is not intended to be an all-inclusive list. Other rationales to support a conclusion of obviousness may be relied upon by Office personnel.
Also, a reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976).
1. Claims 1, 6-9 and 43 are rejected under 35 U.S.C. 103 as being unpatentable over US 2020/0368295 A1 published on Nov. 26, 2020 with PCT filing date of Aug. 7, 2018, (herein after “Santiago”), as evidenced by US 11,395,838 B2, Date of Patent: Jul. 26, 2022, with Provisional Application No. 62/400,372, filed on Sep. 27, 2016 (herein after “Wargo.”).
Regarding a method of mitigating side effects from radiation therapy, the method comprising: (i) identifying a subject to be treated with radiation therapy; (ii) providing a plurality of Lachnospiraceae strains and growing each of said plurality of Lachnospiraceae strains in a separate culture medium under anaerobic conditions for 7 days; (iii) detecting concentrations of butyrate and propionate in culture supernatants from each culture medium from step (ii); (iv) selecting one or more Lachnospiraceae strains that produce butyrate at a concentration higher than about 120 µM and propionate at a concentration higher than about 60 µM; and (v) administering to the subject Lachnospiraceae, from the one or more Lachnospiraceae strains selected in step (iv), wherein side effects from radiation therapy are mitigated in the subject, as recited in instant claim 1:
Santiago teaches methods of treating a subject having gut dysbiosis by administering a pharmaceutical composition comprising a bacterial mixture to treat gut dysbiosis (see Santiago, pg. 45, para[0351]). Santiago’s pharmaceutical composition comprises a bacterial strain derived from any one of the phylum, class, order, family, genus, and/or species listed in Table 5 or Table 6 (see Santiago, pg. 24, para[0160]), such as a bacterial strain belonging to the class Clostridia, belonging to the order Clostridiales, belonging to the family Lachnospiraceae, and belonging to the genus Coprococcus(see Santiago, pg. 24, para[0160]). As evidenced by Wargo, a bacterial strain belonging to the genus Coprococcus, such as the species Coprococcus catus, belongs to the Lachnospiraceae family, Clostridiales order, Clostridia class, Firmicutes phylum (see Wargo, column 35, Table 1). As such the teachings of Santiago suggest a strain of Lachnospiraceae as recited in instant claim 1.
Santiago adds that for subjects who have gut dysbiosis as a side effect of an anti-cancer therapeutic agent and/or a side effect of an anti-cancer therapy, the pharmaceutical composition helps reduce or treat the side effects (see Santiago, pg. 45, para[0352]). Thus, the pharmaceutical compositions find use in reducing, treating or preventing a side effect of an anti-cancer therapeutic agent and/or an anticancer therapy; wherein the anti-cancer therapy may be radiation therapy (see Santiago, pg. 3, para[0029]); thereby constituting a method of mitigating side effects from radiation therapy, and wherein side effects from radiation therapy are mitigated in the subject as recited in instant claim 1. Santiago adds that the subject in need thereof has received, is receiving or will received an anticancer therapeutic agent or therapy (i.e., radiation therapy) (see Santiago, pg. 3, para[0029]); thereby constituting identifying a subject to be treated with radiation therapy; and/or a subject already treated with radiation therapy as recited in instant claim 1.
Santiago’s teachings include confirmation of the viability of the microbiota of the donated stool by culturing a sample of the donated stool and that methods for culturing microbiota from stool or from stool-derived products are well-known in the art (see pg. 9, para[0090]). For instance, microbiota are cultured using the Center for Disease Control (CDC) plate, commonly referred to as “CDC Anaerobe 5% Sheep Blood Agar plate, which allows for the isolation and cultivation of fastidious and slow-growing obligatory anaerobic bacteria (see pg. 9, para[0090]). Santiago includes the diversity of the living microbes in the stool or from stool-derived products may be assayed (see pg. 9, para[0090]). Therefore, Santiago’s teachings read on the newly added claim limitation wherein a plurality of Lachnospiraceae strains are grown under anaerobic conditions.
Santiago also teaches that the mixture of bacterial strains includes one or more bacterial strains that enhance production of one or more of butyrate and propionate (see Santiago, pg. 9, para[0094]); thereby constituting wherein the Lachnospiraceae strains produce butyrate and propionate as recited in instant claim 1. Santiago adds that one or more bacterial strains that produce Short-Chain Fatty Acid (SCFAs) which increase the thickness of the mucus layer, maintain the health of colonocytes, and induce IgA production (see Santiago, pg. 9, para[0094]). Santiago teaches that the mixture of bacterial strains acts to protect, maintain, and restore the gut barrier through inducing a thickening of the colonic epithelial mucus, an increase in IgA production, an increase in antimicrobial peptide production and/or improved tight junction integrity (see Santiago, pg. 37, para[0270]). It is also noted that Tables 5 and 6 include bacteria that belong to the phylum Firmicutes; class Clostridia; order Clostridiales; family Lachnospiraceae; genus Lachnospira (see Santiago, pgs. 12-22). For instance, SEQ ID NOs: 10-11, 32, 40, 41, 48, 49, 53, 67, 74, 77, 80-82, 84, 86-87, 89, 90-92, 94, 99, 101-102, 132-134, 136, 138, 140, 144, 146, 149-150, 153, 157, 160-161, 163, 165, 167-168, 178, 180, 212, 222, 228, 237, 243, 251, 254, 257-258, 301 and 302 from Table 5 and SEQ ID NOs: 536-598 from Table 6 belong to the class Clostridia, family Lachnospiraceae (see Santiago, Table 5 and Table 6). As such, Santiago’s teachings read on the newly added claim limitation wherein a plurality of Lachnospiraceae strains are provided.
Additionally, Santiago teaches that a bacterial strain may be selected for inclusion in the bacterial mixture based on its ability to produce Short-Chain Fatty Acid (SCFAs) or its ability to enhance production of SCFAs, which increases the thickness of the mucus layer, maintains the health of colonocytes, increases butyrate levels in the gut, inhibits nitric oxide synthase activity, reduces the concentration of host-derived nitrate levels in the gut, and/or induces IgA production (see Santiago, pg. 21, para[0136]). Santiago adds that SCFAs refer to fatty acids with an aliphatic tail of less than six carbon atoms and that illustrative SCFAs include, but are not limited to, formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, and isovaleric acid (see Santiago, pg. 21, para[0136]). Accordingly, in some of Santiago’s embodiments, a bacterial strain is selected based on its ability to produce increased levels of SCFAs (see Santiago, pg. 21, para[0136]).
However Santiago des not expressly teach growing each of said plurality of Lachnospiraceae strains in separate culture medium under anaerobic conditions for 7 days, as recited in (ii); detecting concentrations of butyrate and propionate in culture supernatants from each culture medium, as recited in (iii); and selecting one or more Lachnospiraceae strains that produce butyrate higher than about 120µM and propionate higher than about 60µM, as recited in (iv).
With respect to the newly added limitations to claim 1; the MPEP 2112-2112.02 states that when a reference discloses all the limitations of a claim except for a property or function, and the Examiner cannot determine whether or not the reference inherently possesses properties which anticipate or render obvious the claimed invention but has basis for shifting the burden of proof to applicant as in In re Fitzgerald, 619 F.2d 67, 205 USPQ 594 (CCPA 1980). In the instant case, Santiago teaches a mixture of bacterial strains which includes one or more bacterial strains that belong to the class Clostridia, family Lachnospiraceae and enhance production of one or more of butyrate and propionate. The Patent and Trademark Office is not equipped to conduct experimentation in order to determine whether or not the plurality of Lachnospiraceae strains were grown in a separate culture medium under anaerobic conditions for 7 days, concentrations of butyrate and propionate in culture supernatants from each culture medium were detected; and one or more Lachnospiraceae strains that produce butyrate higher than about 120µM and propionate higher than about 60µM were selected. The cited art taken as a whole demonstrates a reasonable probability that Santiago’s mixture of bacterial strains including Lachnospiraceae strains were grown under anaerobic conditions and produce either identical or sufficiently similar amounts of butyrate and propionate to the claimed Lachnospiraceae strains that produce butyrate at a concentration higher than 120µM and propionate higher than about 60µM and that whatever differences exists are not patentably significant. Therefore, with the showing of the reference, the burden of establishing novelty or non-obviousness by objective evidence is shifted to the Applicants.
Additionally, even if Santiago did not expressly teach producing butyrate higher than about 120µM and propionate higher than about 60µM, since Santiago teaches bacteria that belong to the phylum Firmicutes; class Clostridia; order Clostridiales; family Lachnospiraceae; genus Lachnospira thereby constituting well-known Lachnospiraceae strains, the functional properties (i.e., butyrate production higher than about 120µM and propionate production higher than about 60µM) of the Lachnospiraceae strains as claimed and the known Lachnospiraceae bacterial strains would necessarily read upon the same. The discovery of a previously unappreciated property of a prior art composition, or a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer. Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus, the claiming of new functional properties (i.e., butyrate production higher than about 120µM and propionate production higher than about 60µM) which would necessarily read upon the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 4333 (CCPA 1977).
From the teachings of the references, the Examiner recognizes that it would have been prima facie obvious to one or ordinary skill in the art before the effective filing date of the claimed invention to follow the teachings of Santiago and treat a subject having gut dysbiosis as a side effect from radiation therapy by administering a composition comprising a bacterial mixture. One of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to do so because a bacterial mixture comprising a bacterial strain belonging to the family Lachnospiraceae includes one or more bacterial strains that enhance production of one or more of butyrate and propionate; because SCFAs (i.e., butyrate and propionate) increase the thickness of the mucus layer, maintain the health of colonocytes, and induce IgA production; and because the bacterial strain is selected based on its ability to produce increased levels of SCFAs. One of ordinary skill in the art before the effective filing date of the claimed invention would have had a reasonable expectation of success, given that the bacterial mixture was part of a method of treating a subject with gut dysbiosis as a side effect of radiation therapy. Therefore, utilizing a bacterial mixture that comprises Lachnospiraceae strains would support a method of mitigating side effects from radiation therapy, the method comprising administering to the subject Lachnospiraceae strains that produce butyrate higher than about 120µM and propionate higher than about 60µM by constituting the use of known technique to improve similar devices (methods, or products) in the same way and/or applying a known technique to a known device (method, or product) ready for improvement to yield predictable results pursuant to KSR.
Regarding wherein the subject is further administered a metabolite of a strain of Lachnospiraceae, wherein the metabolite comprises one or more tryptophan metabolites, as recited in instant claim 6:
Santiago teaches that the bacterial mixture is administer with and additional therapeutic agent and that the additional therapeutic agent includes, but is not limited to, short-chain fatty acids, butyrate, propionate, acetate, tryptophan, and other tryptophan metabolites (see Santiago, pg. 36, para[0260]), thereby constituting wherein the subject is further administered a metabolite of a strain of Lachnospiraceae, wherein the metabolite comprises one or more tryptophan metabolites as recited in instant claim 6.
Regarding wherein the subject is suffering from side effects from radiation therapy comprising acute radiation syndrome (ARS), hematopoietic (HP) injury, gastrointestinal (GI) injury, cerebrovascular syndrome, cutaneous toxicity, pulmonary toxicity, cardiac toxicity and/or combinations thereof, as recited in instant claim 7:
Santiago teaches that examples of a “side effect of an anti-cancer therapeutic agent" and a "side effect of an anti-cancer therapy" include abdominal pain, anemia and low blood counts, appetite loss, autoimmune effects, bleeding and bruising (thrombocytopenia) (see Santiago, pg. 43, para[320]). In light of the Examiner’s interpretation of hematopoietic (HP) injury and hematopoietic syndrome as discussed in the “Claim Interpretation” section above, the side effects taught by Santiago correlate with the generalized pancytopenia (i.e., significant reduction in the number of almost all blood cells), risk of infection due to neutropenia (i.e., abnormally low count of neutrophils), decreased antibody production and anemia. Thereby the teachings of Santiago constitute wherein the subject is suffering from side effects from radiation therapy comprising hematopoietic (HP) injury (i.e., anemia and low blood counts, bleeding and bruising) and/or gastrointestinal (GI) injury as recited in instant claim 7.
Regarding wherein administration of the Lachnospiraceae effectively attenuates radiation-induced hematopoietic and/or gastrointestinal syndrome, as recited in instant claim 8:
Santiago’s methods treat or reduce a side effect associated with an anti-cancer treatment (i.e., radiation therapy) (see Santiago, pg. 39, para[0285]). Accordingly, the bacterial mixtures are useful in cancer-related applications, at least in decreasing the severity of a side effect and up to eliminating the side effect, e.g., in part, by protecting, maintaining, and restoring the integrity of the gut barrier before, during, and/or after receiving the anti-cancer therapy (see Santiago et al., pg. 39, para[0285]). Thus, the methods of Santiago’s invention reduce, ameliorate, or eliminate one or more symptom(s) associated with a herein-described disease, disorder, or condition (see Santiago et al., pg. 42, para[0314]). Exemplary symptoms include, but are not limited to, diarrhea, bloody stool, mouth sores, perianal disease, abdominal pain, abdominal cramping, fever, fatigue, weight loss, iron deficiency, anemia, appetite loss, weight loss, anorexia, delayed growth, delayed pubertal development, and inflammation of the skin, eyes, joints, liver, and bile ducts (see Santiago, pg. 42, para[0314]). For subjects who have gut dysbiosis as a side effect of an anti-cancer therapeutic agent and/or a side effect of an anti-cancer therapy, the pharmaceutical composition helps reduce or treating the side effect (see Santiago., pg. 45, para[0352]). In light of the Examiner’s interpretation of gastrointestinal syndrome as discussed in the “Claim Interpretation” section above, the side effects taught by Santiago correlate with the impairment of the mucosal membrane of the gut to self-renew, severe nausea, vomiting, diarrhea and even necrosis of the intestines. Thereby the teachings of Santiago constitute wherein administration of the bacterium effectively attenuates radiation-induced hematopoietic (i.e., iron deficiency and/or anemia) and/or gastrointestinal syndrome as recited in instant claim 8.
Regarding wherein the administration of the bacterium Lachnospiraceae to the subject occurs before or after radiation therapy, as recited in instant claim 9:
As previously mentioned, Santiago teaches that the anti-cancer therapy may be surgery, radiation therapy, chemotherapy and/or targeted therapy (see Santiago, pg. 3, para[0029]), and that the subject in need thereof has received, is receiving, or will receive an anti-cancer therapeutic agent and/or an anti-cancer therapy (see Santiago at., pg. 3, para[0029]) thereby encompassing wherein administration of the bacterium to the subject occurs before or after the subject receives or will receive anti-cancer therapy as recited in instant claim 9.
Regarding wherein the one or more tryptophan metabolites are indole-3-carboxyaldehyde and/or kynurenic acid, as recited in instant claim 43:
Santiago’s formulation provides for substantial uniform dissolution of the bacterial strains (and/or additional therapeutic agent) in the area of release in the GI tract (see Santiago, pg. 30, para[210]). Santiago also teaches that in some embodiments, the additional therapeutic agent includes, but is not limited to short-chain fatty acids, butyrate, propionate, acetate, IL-2, IL-22, superoxide dismutase (SOD), GLP-2 and analogs, GLP-1, IL-10, IL-27, TGF-β1, TGF-β2, N- acylphosphatidylethanolamines (NAPEs), elafin (also called peptidase inhibitor 3 and SKALP), trefoil factor, melatonin, tryptophan, PGD2, and kynurenic acid, indole metabolites, and other tryptophan metabolites (see Santiago, pg. 36, para[260]). Therefore, Santiago’s teachings satisfy wherein one or more tryptophan metabolites are indole-3-varboxyaldehyde and/or kynurenic acid as recited in instant claim 43.
In light of the foregoing discussion, the Examiner concludes that the subject matter defined by the above claims would have been obvious to one of ordinary skill in the art within the meaning of 35 USC 103. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references discussed above.
Applicants’ Arguments
Applicants attest that Santiago does not teach or suggest selecting Lachnospiraceae strains that produce butyrate in a culture medium at a concentration higher than about 120µM and propionate in a culture medium at a concentration higher than about 60µM; and that Wargo does is not particularly focused on mitigating the effects of radiation therapy (see Remarks, filed 12/08/2025, pg. 8, last paragraph to pg. 9, 1st paragraph). Applicants contend that Santiago nor Wargo provide any experimental data for a subject treated with bacteria and radiation, and that one of ordinary skill in the art could not have predicted the superior results described in the instant specification for subjects treated with ration who have received Lachnospiraceae from strains that particularly produce the instantly recited concentrations of butyrate and propionate instead of from other strains of Lachnospiraceae (see Remarks, filed 12/08/2025, pg. 10, second paragraph).
Applicants also assert that claim 1 has been amended and that the subject application provides sufficient description regarding the selection and administration of Lachnospiraceae from strains that produce the claimed concentration of butyrate and propionate; therefore claim 1 and its dependent claims 6-9 are sufficiently supported by the specification as filed to meet the written description requirement of 35 U.S.C. 112(a) (see Remarks, filed 12/08/2025, pg. 10 last paragraph and pg. 11, paragraphs 1-3).
Response to Arguments
Applicants' arguments filed 12/08/2025, with respect to 35 U.S.C. 112(a) first paragraph as failing to comply with the written description requirement, have been fully considered but they are not persuasive for the following reasons:
MPEP §2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
In the instant case, the details provided in the instant specification pertaining to the Lachnospiraceae strains that produce butyrate higher than about 120µM and propionate higher than 60µM fail to convey with reasonable clarity that the inventors had possession of the specific strains of Lachnospiraceae that yield the higher amounts of butyrate and propionate. The evidence provided in the specification is not sufficient to satisfy the written description of a genus (i.e., Lachnospiraceae) because the “identifying characteristics” described in the instant specification, in particular Fig. 6A and Fig. 6B and pg. 9, lines 10-24; and pg. 33, line 29 to pg. 34, line 7, refer to Lachnospiraceae strains that produced low SCFAs (i.e., strains 8, 9, and 21) and to the strains that produced high SCFAs (i.e. ,strains 2, 14, and 20). Additionally, Figs. 6A depicts the concentration of SCFA (µM) produced by six strains (i.e., Lachno 8, Lahcno 9, Lachno 21, Lachno 2, Lachno 14 and Lachno 20) that produce SCFA and have been categorized by Applicants as “Lachno Low SCFA Producers” and “Lachno High SCFA producers”. However, there is no core structure/sequence (i.e., amino acid sequence and/or nucleic acid sequence) that can be traced to or associated with the Lachno high or Lachno low producing SCFAs strains nor a representative number of species by actual reduction to practice. Therefore, an ordinary skill artisan would conclude that Applicants were not in possession of the claimed Lachnospiraceae strains because Lachno 8, Lahcno 9, Lachno 21, Lachno 2, Lachno 14 and Lachno 20 could be any member of the Lachnospiraceae family, since the instant specification fails to teach a sequence and/or core structure for the Lachno Low SCFA producers and the Lachno High SCFA producers that exhibits the function of producing butyrate at a concentration higher than about 120 µM and propionate at a concentration higher than about 60 µM.
In other words, it is not readily apparent which Lachnospiraceae strains would results in higher SCFAs and which ones would not because the scope of the claimed invention encompasses any Lachnospiraceae strains. As previously mentioned Lachnospiraceae family is a phylogenetically and morphologically heterogenous taxon belonging to the clostridial cluster XIVa of the phylum Firmicutes (see Vacca et al., Microorganisms 2020, 8, 573, pp. 2-25 at pg. 2, first paragraph), and the Lachnospiraceae family currently comprises 58 genera and several unclassified strains (see Vacca, bottom of pg. 2). Therefore, any of the 58 members or unclassified strains of the Lachnospiraceae family could be high SCFA producers. Additionally, a "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, the limited Lachnospiraceae strains referred to in Fig. 6B do not constitute a representative number of strains that an ordinary skilled artisan can reasonably extrapolate which strains would exhibit the claimed function.
Furthermore, the evidence provided the instant specification in particular Example 8 and Example 9, is also not sufficient to satisfy the written description requirement because the Examples refer to Lachnospiraceae strains without referencing to a specific species belonging to the Lachnospiraceae family and without identifying a necessary core structure and/or sequence (i.e., amino acid sequence or nucleic acid sequence) that would exhibit the function of producing higher amounts of butyrate and propionate. Therefore, the “identifying characteristics” recited in the instant specification are not sufficient to distinguish the claimed Lachnospiraceae strains from other known SCFA producing strains that belong to the Phylum Firmicutes, Class Clostridia, Order Clostridiales, Family Lachnospiraceae. As such, the details disclosed in the instant specification pertaining to the “identifying characteristics” are not sufficient to show that Applicants were in possession of the claimed genus (i.e., Lachnospiraceae), and are also not sufficient to claim that the Applicants’ were in possession of the claimed species (i.e., strains that produce butyrate higher than about 120µM and propionate higher than 60µM). Accordingly, the 35 U.S.C. 112(a) rejection of claims 1, 6-9 and 43 is maintained.
Applicants' arguments filed 12/08/2025, with respect to 35 U.S.C. 35 U.S.C. 103 as being unpatentable over US 2020/0368295 A1 published on Nov. 26, 2020 with PCT filing date of Aug. 7, 2018, (herein after “Santiago”), as evidenced by US 11,395,838 B2, Date of Patent: Jul. 26, 2022, with Provisional Application No. 62/400,372, filed on Sep. 27, 2016 (herein after “Wargo.”); have been fully considered but they are not persuasive for the following reasons:
It is acknowledged that there is not a single reference that teaches and/or suggests every claim limitation recited in instant claim 1 and its dependent claims 6-9. However, Applicants are respectfully reminded that the rejections supra are based on obviousness. Pursuant to MPEP 2142, 35 USC 103 authorizes a rejection where, to meet the claim, it is necessary to modify a single reference or to combine it with one or more other references (emphasis added). Since the rejection is based on obviousness, it is unnecessary for every claim limitation to be taught and/or suggested by a single reference. Additionally, the Examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
As discussed above in the 35 U.S.C 103 rejection above, Santiago teaches pharmaceutical compositions comprising bacterial strains belonging to the class Clostridia, order Clostridiales, family Lachnospiraceae, genus Coprococcus. Santiago also teaches that the compositions help reduce or treat side effects of an anti-cancer therapeutic agent and/or a side effect of an anti-cancer therapy; wherein the anticancer therapy may be radiation. Wargo provides evidence that a bacterial strain belonging to the genus Coprococcus, such as the species Coprococcus catus, belongs to the Lachnospiraceae family, Clostridiales order, Clostridia class, Firmicutes phylum. Therefore, Santiago’s composition comprising Lachnospiraceae strains reads on the instantly claimed method of mitigating side effects from radiation therapy. As such, the question is (1) whether a person of ordinary skill in the art would be motivated and/or expected that the pharmaceutical composition as taught by Santiago mitigates the side effects from radiation therapy, and (2) whether a person of ordinary skill in the art would be motivated and/or expected to administer Lachnospiraceae strains that produce butyrate and propionate to a subject having side effects from radiation therapy. The Examiner maintains that the answers to these questions are yes in light of the teachings of Santiago and Wargo for questions one and two
Furthermore it is the Examiner’s understanding that Applicants’ statements amount to a suggestion that the prior art is not fully enabled or operable (see Remarks, filed 12/08/2025, pg. 10, paragraph 2, stating that Santiago does not provide any experimental data for a subject treated with bacteria and radiation). If Applicant is attempting to allege that the prior art is not enabling or inoperable Applicant is directed to MPEP § 2121(I), which notes that the prior art is presumed fully enabled for all that it discloses, and the burden is on the Applicant to rebut the presumption of operability (see, e.g., MPEP § 2121(I); MPEP § 716.07). No evidence of inoperability commensurate in scope with the requirements of MPEP § 716.07 have been placed on record at this time; critically, arguments of counsel cannot take the place of evidence in the record (see, e.g., In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965), and evidence is required to rebut the presumption of operability. As such, it is not necessary for the cited prior art to provide experimental data for a subject treated with bacteria and radiation, because the teachings of Santiago read on the instantly claimed method of mitigating side effects from radiation therapy by administering to a subject Lachnospiraceae strains which produce butyrate and propionate.
With respect to Applicants’ assertion that one of ordinary skill in the art could not have predicted the superior results described in the instant specification for subjects treated with radiation who had received Lachnospiraceae from strains that particularly produce the instantly recited concentrations of butyrate and propionate instead of from other strains of Lachnospiraceae (see Remarks, filed on 12/08/2025, pg. 10, second paragraph).
The Examiner is interpreting Applicants’ assertion as evidence of unexpected results. However, Pursuant to MPEP 716.02(b)(I), the evidence relied upon should establish “that the differences in results are in fact unexpected and unobvious and of both statistical and practically significance.” Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions in appellants’ brief that the claimed polymer had an unexpectedly increased impact strength “are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration.”). See MPEP 716.02(b)(I). Additionally, MPEP 716.02(c)(II), states that expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof." In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967).
In the instant case, mitigating the side effects from radiation therapy in a subject is an expected result of administering Lachnospiraceae strains to a subject that has received or will receive radiation therapy since Santiago’s bacterial mixture comprising a bacterial strain belonging to the family Lachnospiraceae includes one or more bacterial strains that enhance production of one or more of butyrate and propionate; since SCFAs (i.e., butyrate and propionate) increase the thickness of the mucus layer, maintain the health of colonocytes, and induce IgA production; since the bacterial strain is selected based on its ability to produce increased levels of SCFAs, and since the bacterial mixture was part of a method of treating a subject with gut dysbiosis as a side effect of radiation therapy.
Therefore, contrary to Applicant’s argument, the Examiner maintains that a person of ordinary skill in the art would have been motivated with reasonable expectation of success to utilize a bacterial mixture comprising Lachnospiraceae strains as part of a method of mitigating the side effects from radiation; thereby rendering the instantly claim method obvious with a reasonable expectation of success.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/CLAUDIA ESPINOSA/Patent Examiner, Art Unit 1654
/LIANKO G GARYU/Supervisory Patent Examiner, Art Unit 1654