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 with traverse of species: dysbiosis in the reply filed on 1/06/2026 is acknowledged. The traversal is on the ground(s) that claim 56 reads on elected species, and this species can be regarded to apply to all claims because all claims can or do involve dysbiosis. This is not found persuasive because claim 56 is itself a dependent claim and the other claims that Applicant speaks of are dependent on claim 55. These claims (that are dependent on claim 55) may be independent from dysbiosis.
Applicants further argue that the reference relied upon to indicate lack of unity was not correctly interpreted. Examiner agrees. The reference relied upon is directed to an invention requiring an inhibitor of HSP90 while instant invention is directed to expressing HSP90. However, as Applicants will see, instant Office Action relies on the references of Cohen and Gill. The combined references do make obvious an invention of treating dysbiosis. Therefore, the species election requirement is maintained.
Further, Applicants argue all claims must be kept together. Applicant need not ask. On allowability of selected claims, all unselected claims will be examined.
The requirement is still deemed proper and is therefore made FINAL.
Claims 61-65 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 1/06/2026.
Claims 55-60 and 66-74 are being examined.
Claim Rejections - 35 USC § 112
Claim 66 is rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of one antibiotic, probiotic or prebiotic agent, as recited in claim 66 is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: antibiotics are drugs utilized to inhibit bacteria, probiotics are bacteria, and prebiotics are agents that promote bacteria. Therefore, a grouping such as instant is a grouping of alternatives that are known to have opposite effects.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 112(a)
Written Description
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.
Claims 55-60 and 66-74 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The purpose of the written description requirement is to “ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997).
An original claim may lack written description support when a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). 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, reduction to drawings, 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. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See MPEP 2163.
Scope of the Invention
In the instant case, the genera are:
Active fragment thereof (claims 55 and 74)
The broadest reasonable interpretation of the scope of the genera listed above is a nucleic acid sequence encoding a mammalian heat shock protein 90 (HSP90), or fragment thereof, such that the fragment retains its ability to modulate host microflora. This interpretation is based on description on pg. 19, section on Heat shock protein 90 (HSP90) and constructs encoding same. Further, the description states: the encoded polypeptide is characterized as retaining immunological cross-reactivity with mammalian and bacterial HSP (e.g. containing cross-reactive T-reg epitopes of mammalian and microbial HSP90).
Disclosure of a Complete or Partial Structure
Regarding active fragment thereof, the inventive concept requires the HSP and fragments to retain their ability to modulate host microflora. Further description includes NCBI ref seq IDs for full-length HSP isoforms. The working examples describe a recombinant construct encoding human HSP90 (alpha isoform 2) under CMV promoter expression control was constructed based on the pCDNA3.1 expression vector (pg. 36, Fig. 1). They go on to show that such a plasmid, when injected intramuscularly into a mouse has a positive effect on dysbiosis in mice (Examples 1-3). An unexpected specific modulation of tumor necrosis factor alpha (TNF-a) levels was also seen on administration of the HSP90 plasmid (Example 4). However, it is not clear how an active fragment of HSP90 correspond to these superiorly working full-length HSP90. It is not clear how the full-length HSP90 may be varied so that they retain just the essential conserved domains yet retain the function that defines them; i.e., modulate host microflora, as described by the rest of the disclosure.
Structure/Function Correlation
Regarding the genera, as discussed above, Applicant’s claims encompasses particular fragments of the full-length HSP90 with the proviso that they allow for those fragments, working alone or in combination with other agents, to modulate host microflora [Summary of Invention, pg. 3], while only full-length HSP90 are described in the instant specification without any correlation to what core sequence is encompassed by the term fragment that is recited. The breadth of the claimed genera is enormously broad with an unfathomable number of structurally divergent and diverse fragments.
Regarding all the fragments claimed, Applicant has not demonstrated possession of any fragment that could be called an active fragments that will still work in the method claimed, other than the full-length HSP90. The examples described do not provide support for the entire genus/subgenera of fragments claimed because the examples show only full-length HSP90 species. The Specification does not provide sufficient evidence that each member of the entire genus of HSP90 claimed would produce the intended outcome of modulating host microflora. The Specification does not provide specific guidance for determining what the structure of species of fragments should be that will work as expected; the functional characteristic is not coupled with a known structure.
The Spec. does not identify a core structure necessary for being an active fragment.
Altogether, the number of species disclosed by complete structure is not sufficient to provide the written description support for the huge genus of heat shock protein 90 (HSP90) fragments and constructs encoding same claimed.
These are broad genera with diverse members and different structures that underly their functions. Although the claims recite compounds that inherently possess a functional characteristic, i.e., modulate host microflora, the functional characteristic is not coupled with a known structure.
Knowledge from the Art
Srivastava (US 20010034042 A1, IDS), which would be considered within the scope of invention teaches fragments of HSP90. Srivastava teach a heat shock protein fragment is one that lacks one or more other domains of the heat shock protein. Srivastava use such fragments for their immunomodulatory properties. Thus, one can eliminate a domain of HSP90 and yet obtain a functional immunomodulatory peptide. However, nothing in the art teaches one of skill how to vary the HSP90 so that a fragment that is an active fragment that can modulate host microflora be obtained.
Dependent Claims
Claims 56-60 and 66-73 do not further limit the genus of active fragments so as to resolve the issues above, and are therefore, not sufficiently described for at least the reasons above.
Conclusion of Written Description
Therefore, the examiner concludes there is insufficient written description support for the instantly claimed genera of active fragments of HSP90 as stated. Only full-length HSP90 but not the full breadth of the claims is supported by Applicant’s disclosure.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 55-56 and 67-70 are rejected under 35 U.S.C. 103 as being unpatentable over Cohen (Cohen et al., WO 2018178767, cited in IDS) in view of Gill (Gill et al., Arthritis Rheumatol. 2018 Mar 7;70(4):555–565).
Claim interpretation: The term "dysbiosis" as recited in claim 56 refers to a state of the microbiota of the gut or other body area in a subject, in which the normal diversity and/or function of the microbial populations is disrupted (pg. 12, last para).
Regarding claims 55 and 56, Cohen teach a method of treating an autoimmune inflammatory disease comprising administering to an HLA-B27 positive subject an immunogenic composition comprising a recombinant construct of a nucleic acid sequence encoding a heat shock protein 90 (HSP 90) wherein the nucleic acid sequence is operatively linked to one or more transcription control sequences, thereby treating the inflammatory disease (Cohen claim 1 and abstract; CMV promoter, [0060]). Cohen teach wherein the inflammatory disease is a spondyloarthropathy, wherein the spondyloarthropathy is anklyosing spondylitis, reactive arthritis, psoriatic arthritis or enteropathic arthritis (Cohen claims 2-4). Cohen teach wherein the subject is HLA-B27 positive. Cohen teach the method results in an anti-inflammatory effect on experimental rats (FIGS. 5A and 8B, a trend toward a decrease in the signs of arthritis was observed in transgenic HLA- B27 treated rats as compared to transgenic HLA-B27 control rats at day 24 and day 31. In HLA-B27 treated rats an improvement in these signs of arthritis was also observed was observed at day 17 and day 21 of treated animals as compared to the beginning of the study).
Regarding claim 67, Cohen teach the HSP is human HSP90 (Cohen claim 15).
Regarding claim 68, Cohen teach the construct is in a pharmaceutical composition (Cohen claims 26-27).
Regarding claim 69, Cohen teach the construct is administered naked [0064].
Regarding claim 70, Cohen teach the construct can be administered by intramuscular route (Cohen claim 17-18).
Cohen lack a teaching on microbiota and dysbiosis (claim 55-56) but state this about ankylosing spondylitis is “one of the strongest known associations of disease with HLA-B27” [0002].
Gill teach that HLA-B27 is associated with major shifts in gut microbial composition (pg. 10, paragraph 1). Gill teach, three experimental animal models, Lewis, Fischer, and Dark Agouti (DA), of HLA-B27-mediated spondyloarthritis (SpA) (ankylosing spondylitis (AS) is the prototype of SpA) display similar immune dysregulation pathways but different patterns of dysbiosis (abstract).
See recitation from abstract:
Results
HLA-B27 transgenic Lewis and Fischer rats develop gut inflammation, while DA rats are resistant to effects of HLA-B27 ….DA rats lack segmented filamentous bacteria (SFB) that promote CD4+ Th17 T-cell development, which may explain their resistance to disease.
Gill further teach that the microbes that are increased in the mice that develop HLA-B27-mediated disease are the microbes that have been previously associated with gut inflammation: Akkermansia muciniphila (p_Verrucomicrobia) on Fischer and Prevotella (p_Bacteroidetes) on Lewis strains (pg. 10, paragraph 2). Gill further teach, control HLA-B7 transgenic rats do not show gut inflammation or dysbiosis (pg. 5, paragraph 1). Gill further teach HLA-B27 drives dysbiosis in a background-specific fashion (major differences in microbe diversity between the Lewis and Fischer backgrounds, Figure 6A). Thus, Gill make a case for dysbiosis in HLA-B27-mediated disease and dysbiosis (title).
As such, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have used a recombinant construct of a nucleic acid sequence encoding a heat shock protein 90 (HSP 90) as in the method of Cohen to modify microbiota diversity and treat dysbiosis since the method was already known and effective in treated HLA-B27-mediated disease and Gill had taught HLA-B27-mediated disease is also associated with dysbiosis. The selection of a known material based on its suitability for its intended use supports a prima facie obviousness determination as taught in MPEP 2144.07. The claimed method of treating to modify microbiota diversity is closely related and associated with the method of treating an HLA positive individual.
Thus, Cohen in view of Gill make obvious instant claims 55-56 and 67-70.
Claims 57-60, 66, and 71 are rejected under 35 U.S.C. 103 as being unpatentable over Cohen (Cohen et al., WO 2018178767, cited in IDS) in view of Gill (Gill et al., Arthritis Rheumatol. 2018 Mar 7;70(4):555–565) as applied to claims 55-56 and 67-70 above and further in view of Pitt (Pitt et al, Immunity, Volume 44, Issue 6, 21 June 2016, Pages 1255-1269) and evidenced by Auclair (Auclair et al., Clin. Infect. Dis., 60 (Suppl 2) (2015), pp. S135-S143).
The method of treating to modify microbiota diversity by administering HSP90 was made obvious by Cohen and Gill above and is incorporated herein.
Cohen and Gill lack teachings on the beneficial microbiota recited and resistance to immunomodulatory treatment.
However, before the effective filing date of instant invention, Pitt had taught several factors are responsible for Resistance Mechanisms to Immune-Checkpoint Blockade (ICB) in Cancer: Tumor-Intrinsic and -Extrinsic Factors (title). Pitt teach the host microbiota can determine responses to cancer therapies (introduction, Section on The Gut Microbiota and Immune “Fitness”, pg. 1260 - 1263). Pitt teach several studies have shown how distinct bacteria, or bacterial products, can promote alterations in immune responses. Pitt teach Influence of Gut Microbiota on ICB Immunotherapy. Pitt teach Immune-Checkpoint Blockade through Manipulating the Microbiome. Pitt teach the reinstating of defective anti-cancer T cell responses, is derived from immune sensing of the bacterial species present at that particular time in the microflora. Pitt teach mucosal (re)colonization with live (and not dead) immunogenic bacteria (capable of eliciting bacteria-specific Th1 cell immune responses), such as E. hirae or B. fragilis either alone or combined with B. cepacia or Bifidobacterium, is required for reinstating anti-cancer adaptive T cell responses.
Regarding claims 57 and 58, Pitt teach CTLA-4 blockade (Immunotherapy using Immune Checkpoint Blockers) induces the accumulation of distinct Bacteroides spp. in the inner part of the mucus layer. Pitt teach tolerogenic Bacteroides species mediate complete resistance; i.e., are detrimental.
Regarding claims 59 -60, Pitt cite Auclair et al., 2015 on pg. 1264, middle of page on left. As evidenced by Auclair, a lack of microbial diversity in the host gut is detrimental to endogenous immune activation (introduction, Auclair). Auclair evidences a specific probiotic combination composed of L. acidophilus CL1285, L. casei LBC80R, and L. rhamnosus as co-therapy (Conclusion para of Auclair).
Regarding claim 66, Pitt teach a specific probiotic formulation consisting of one or several of these immunogenic commensals (considering a choice of the most effective isolates of these species) would be necessary for testing in preclinical models and clinical trials to prevent or compensate for primary resistance to ICBs (Figure 3).
Regarding claim 71, Pitt teach a method of modifying gut microbiota is suitable for use in subjects that have developed resistance to immunomodulatory treatment (Mobilizing the Gut Microbiota to Circumvent Primary Resistance to ICB in Patients, Figure 3).
It would have been prima facie obvious to one of ordinary skill in the art at the time of the instant invention to apply the method of Cohen and Gill to the circumstances taught by Pitt and have a reasonable expectation of success. One would have been motivated to do so since Pitt teach such conditions (resistance to immunomodulatory therapy) are also mediated via a dysregulated immune system. Further, Pitt had provided teachings for modifying gut microbiota, such teachings are easily implementable by one of skill in the art, as at the simplest level such modifying merely requires dietary changes. The selection of a known material based on its suitability for its intended use supports a prima facie obviousness determination as taught in MPEP 2144.07.
Thus, Cohen and Gill in view of Pitt make obvious instant claims 57-60, 66, and 71.
Claims 72-73 are rejected under 35 U.S.C. 103 as being unpatentable over Cohen (Cohen et al., WO 2018178767, cited in IDS) in view of Gill (Gill et al., Arthritis Rheumatol. 2018 Mar 7;70(4):555–565) as applied to claims 55-56 and 67-70 above and further in view of Chen (US 20240293504 A1 with a priority date of 22nd Jun 2020) and Le Tourneau et al. (Dose escalation methods in phase I cancer clinical trials. J Natl Cancer Inst. 2009 May 20;101(10):708-20.).
The method of treating to modify microbiota diversity by administering HSP90 was made obvious by Cohen and Gill above and is incorporated herein.
Cohen and Gill lack teachings on TNFa inhibitors or schedules.
Specifically, Cohen and Gill lack teachings on TNF-a antagonist or inhibitor (claim 72), which is selected from the group consisting of adalimumab, certolizumab, certolizumab pegol, golimumab, infliximab and etanercept (claim 73) or manner of administration (claim 72).
However, before the effective filing date of instant invention, Chen had taught a method of treating cancer in a subject comprising administering compositions comprising a recombinant polypeptide and/or nucleic acids and at least one at least one other agent [title, [0009]). Chen teach release of HSP90 from tumors or their environments on treatment with the recombinant polypeptide (Fig. 11-13). Therefore, Chen teach a method of treating cancer in a subject comprising administering compositions comprising a recombinant polypeptide and the at least one other agent is a TNFalpha inhibitory agent [title, [0009]). Chen disclose TNFa receptor, infliximab, adalimumab, certolizumab pegol, golimumab and Enbrel as TNFa inhibitor agents ([0066]). Chen teach their method is capable of treating breast, lung, and colon cancer as well as melanoma (see Examples 2, 4, 11, and 12). Chen teach their method is capable of treating non-cancerous conditions or disorders, an exemplary list of which is provided [0214]. Thus, the cancers or non-cancers that fall within the scope of Chen’s invention are diseases characterized by inflammation [0340].
Regarding claims 72 – 73, Chen teach a method comprising administering to the subject: a composition comprising one Tumor Necrosis Factor alpha (TNFa) inhibitory agent; and a composition comprising a recombinant polypeptide or a nucleic acid encoding the recombinant polypeptide and other agents(Chen claim 1). Since Chen’s method is treating inflammation, it is related to instant invention.
Therefore, it would be prima facie obvious to add the TNFa inhibitor agent compositions taught by Chen to the method of treating described by Cohen and Gill to further improve the latter’s treatment by combining multiple therapeutics useful for the same purpose. One skilled in the art would have a reasonable expectation of success because all of the compositions had been used to treat the same underlying immune dysregulation. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted). See MPEP 2144.06(I).
Neither of the references cited above explicitly teach administering one composition prior to another composition in a certain order (schedule) or dosages. Le Tourneau, however, teaches dosage optimization in phase I cancer clinical trials (Title, Abstract). Le Tourneau explains that in rule-based phase I trials of drug combinations, the dose level of each drug may be based on several factors such as preclinical data, current tumor-specific standard treatments, the expected control arm if the combination of drugs under evaluation may be benchmarked by future randomized trials, and/or empiricism (Pg 715, “Designs for trials of combinations of agents, second paragraph). Bayesian modeling as well as pharmacokinetic analyses may further provide information regarding toxicities and interactions between different anticancer drugs administered in combination (third and fourth paragraphs). All of these decisions impact the recommended schedules and dosages, which can determine the success or failure of a combination. Thus, while Cohen, Gill and Chen make obvious instant claims 71-72, they do not explicitly teach the schedules or dosages claimed, it would have been prima facie obvious to one of ordinary skill in the art because Le Tourneau recognized that scheduling and dosing of combinations of therapeutics depended on a number of factors, as described above. Thus, it would have been obvious to optimize the dosage schedule and dosages as claimed in order to effectively treat cancer. See MPEP 2144.05(II).
Thus, Cohen and Gill in view of Chen and Le Tourneau make obvious instant claims 72-73.
Claim 74 is rejected under 35 U.S.C. 103 as being unpatentable over Dokladny (Dokladny et al., Am J Physiol Gastrointest Liver Physiol 290: G204–G212, 2006) in view of Cohen (Cohen et al., WO 2018178767, cited in IDS) and Gill (Gill et al., Arthritis Rheumatol. 2018 Mar 7;70(4):555–565).
Claim Interpretation: gut barrier dysfunction, is being interpreted as: an increase in intestinal permeability associated with GI dysbiosis (pg. 3, 2nd para).
Dokladny teach HSP are protective in maintaining the intestinal epithelial tight junction (TJ) barrier. See recitation from last line of abstract:
HSPs play an important protective role in preventing the heat-induced disruption of intestinal TJ barrier and suggest that HSP mediated upregulation of occludin expression may be an important mechanism involved in the maintenance of intestinal epithelial TJ barrier function during heat stress.
Dokladny teach HSP90’s protective role in a Caco-2 intestinal epithelial model system, wherein cells exposed to heat were found to result in a significant time- and temperature-dependent increase in TJ permeability, and rapid and sustained increases in HSP expression; and inhibition of HSP expression produced a marked increase in heat-induced increase in Caco-2 TJ permeability (abstract). Quercetin as a HSP inhibitor and cycloheximide (CHX) as protein synthesis inhibitor were tested. See Figs. 1 and 3-10. Dokladny further teach, heat stress has many biological effects in animals including inducing hypoperfusion of intestinal vasculature, activation of various inflammatory cascades and immune mediators , activation of apoptosis, activation of humoral system , and generation of oxygen free radicals that are known to affect the intestinal TJ barrier (pg. G205, l col, 2nd para). Dokladny teach an intact intestinal epithelial TJ barrier is crucial in providing barrier function against paracellular penetration of pathogenic bacteria (pg. G204, l col, 1st para). Thus, Dokladny teach an HSP containing environment would be protective for gut barrier dysfunction.
Dokladny lack a teaching on a construct encoding HSP90.
However, before the effective filing date of instant invention, Cohen and Gill had taught a method resulting in modifying microbiota diversity by administering HSP90. Such method was discussed above and is incorporated herein.
Therefore, it would be prima facie obvious to administer the construct of HSP90 as taught by Cohen and Gill in a method to treat and prevent gut barrier dysfunction as Dokladny provide the teachings and motivation to do so. Further, Dokladny had taught that maintaining an intact gut barrier was essential to protect against pathogenic bacteria, the latter shown to be implicated in dysbiosis by Gill. One skilled in the art would have a reasonable expectation of success because the composition used in the method would be performing the same function in the method of Dokladny as it was in the method of Cohen and Gill. Generally, it is prima facie obvious to select a known material for incorporation into a composition, based on its recognized suitability for its intended use. See MPEP 2144.07 and 2143 G.
Thus, Dokladny in view of Cohen and Gill make obvious instant claim 74.
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
Conclusion
No claims are allowed.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SHABANA MEYERING, Ph.D. whose telephone number is (703)756-4603. The examiner can normally be reached M - F: 9am to 5pm EST.
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SHABANA S. MEYERING, Ph.D.
Examiner
Art Unit 1635
/SHABANA S MEYERING/ Examiner, Art Unit 1635
/CATHERINE KONOPKA/ Primary Examiner, Art Unit 1635