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 .
Foreign Priority
Acknowledgment is made of applicant's claim for foreign priority based on an application filed in India on 10/11/21. It is noted, however, that applicant has not filed a certified copy of the IN202131046340 application as required by 37 CFR 1.55.
Priority
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, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 365(c) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. PCT/IB2021/061243, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. The application does not disclose that the extra polymeric substances are derived from gram-positive non-pathogenic Bacillus velezensis MTCC25513.
Should applicant disagree, applicants are encouraged to point out with particularity by page and line number where such support might exist. Therefore, the effective filing date of the instant claims is considered, for purposes of prior art, to be 4/10/24, which is the filing date of the instant application.
Specification
The disclosure is objected to because of the following informalities: Table 3 on page 24 and Table 4 on page 25 are not legible.
Appropriate correction is required.
The specification is objected to as failing to provide proper antecedent basis for the claimed subject matter. See 37 CFR 1.75(d)(1) and MPEP § 608.01(o). Correction of the following is required: The specification does not disclose that the extra polymeric substances are derived from gram-positive non-pathogenic Bacillus velezensis MTCC25513.
Claim Objections
Claims 23-27, 29, 31, and 34-37 are objected to because of the following informalities: In claim 23, part (b), it appears that applicant inadvertently omitted a comma between propionic acid and small peptides (propionic acid, and small peptides), which alters the claim from short fatty acids including propionic acid to short fatty acids including propionic acid and small peptides. Appropriate correction is required.
In claim 24, it appears that applicant inadvertently omitted a space between concentration and 0.9%. Appropriate correction is required.
In claim 25, it appears that applicant inadvertently omitted the word “an” between “vesicle” and “is”. Appropriate correction is required.
In claim 26, it appears that applicant inadvertently omitted the word “and” between cRNA and piRNA. Appropriate correction is required.
In claim 29, it appears that applicant inadvertently omitted the word “and” between CCL-11 and CCL-2. Appropriate correction is required.
In claim 31, it appears that applicant inadvertently omitted the word “is” after (exRNA) and after saline and after ethanol. Appropriate correction is required.
In claim 34, it appears that applicant inadvertently omitted the word “and” before Phosphate buffer saline and before pH. Appropriate correction is required.
In claim 35, it appears that applicant inadvertently omitted a space after 1000 (before rpm). Appropriate correction is required.
In claim 36, it appears that applicant inadvertently omitted a space after 4500 (before rpm). Appropriate correction is required.
In claim 37, it appears that applicant inadvertently omitted a space between 0.22 and µm. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 23-42 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 23 and 28 recite “short fatty acids including propionic acid”. The claim is indefinite because the metes and bounds of the genus cannot be clearly ascertained. It is unclear whether propionic acid is required or not and what other alternatives are intended to be encompassed by the claim.
Additionally, the claims require for the extra polymeric substances to be “derived from gram-positive non-pathogenic Bacillus velezensis MTCC25513”. However, the metes and bounds of the term “derived” are not definite. It is unclear what specific structure is required for the EPS.
Claims 26, 29, and 34 recite “selected from the group comprising” rather than “selected from the group consisting of” and therefore it is unclear what other alternatives are intended to be encompassed by the claim or if one of the recited species is in fact required or not.
Claims 32 and 38 are directed to a method of treating autoimmune diseases “including” the recited species. The claim is indefinite because the metes and bounds of the genus cannot be clearly ascertained. It is unclear whether all of the species are required or not and what other alternatives are intended to be encompassed by the claim.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 41 and 42 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Dependent claims are required to include all limitations of the base claim and an additional limitation. Claims 41 and 42 require the anti-inflammatory composition of the base claim but do not recite any additional structural limitation. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 23-42 are rejected under 35 U.S.C. 112, 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(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
The newly added claims recite that the extra polymeric substances are derived from gram-positive non-pathogenic Bacillus velezensis MTCC25513. Although the amended claims were filed on the same day as the originally filed claims, the claim limitations are not supported by the originally filed specification.
MPEP §2163.06 notes:
If new matter is added to the claims, the examiner should reject the claims under 35 U.S.C. 112, first paragraph - written description requirement. In re Rasmussen, 650 F.2d 1212, 211 USPQ 323 (CCPA 1981).
MPEP §2163.02 teaches that:
Whenever the issue arises, the fundamental factual inquiry is whether a claim defines an invention that is clearly conveyed to those skilled in the art at the time the application was filed...If a claim is amended to include subject matter, limitations, or terminology not present in the application as filed, involving a departure from, addition to, or deletion from the disclosure of the application as filed, the examiner should conclude that the claimed subject matter is not described in that application.
A review of the specification does not reveal support for where the claim limitations are found. Should applicant disagree, applicants are encouraged to point out with particularity by page and line number where such support might exist for each claim limitation added in the amended claims filed on 4/10/24.
There is no support for this claim limitation in the claimed priority documents. Therefore, the effective filing date of the instant claims is considered, for purposes of prior art, to be 4/10/24, which is the filing date of the instant application.
Claims 23-42 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 claims are directed to a composition comprising any exRNA encapsulated in any EV, each being derived from gram-positive non-pathogenic Bacillus velezensis MTCC25513.
The instant specification does not adequately describe the genus of exRNA that can be encapsulated in any possible EV, each being derived from gram-positive non-pathogenic Bacillus velezensis MTCC25513.
For example, rRNA can be derived from gram-positive non-pathogenic Bacillus velezensis MTCC25513 and would not meet the size constraints of many EVs. Additionally, non-vesicle rRNAs would not necessarily meet the size constraints of many EVs.
O’Brien et al. (Nature Reviews. Molecular Cell Biology, 21, 2020, 585-606) teach that the transcriptomes of different cell types are partially reflected in their extracellular vesicle RNA cargo, but the RNA profiles of extracellular vesicles differ substantially from those of their cells of origin, suggesting that some RNA species are selectively incorporated into extracellular vesicles (page 588).
O’Brien et al. teach: Small size, high abundance, ability to associate with membranes and cytoplasmic (versus nuclear) location favour incorporation of a given RNA into extracellular vesicles (page 589).
O’Brien et al. teach: Thus, many mechanisms can influence packaging of RNAs into extracellular vesicles, but the extent to which these mechanisms are specific to selected RNA species and how RNA cargo loading is regulated by the cells remain elusive (page 590).
Additionally, the specification does not adequately describe the genus of exRNA and EVS that are “derived” in any manner from gram positive non-pathogenic Bacillus velezensis MTCC25513 and have the recited function of downregulating inflammatory genes.
The specification does not adequately describe the specific structure required for the exRNA and for the EV to achieve the function of downregulating of any possible inflammatory genes.
The specification does not adequately describe the genus of exRNAs and EVs.
Claim 33 requires suspension of EPS substances. The specification does not adequately describe the structure required for an agent to be an EPS substance or what specific compound is required. Additionally, the claim recites biofilm-associated extra polymeric substances, which is a genus that has not been adequately described in the specification. The specification does not adequately describe what structural relationship is required for the EPS to be associated in any manner to biofilm.
Regarding claims 39 and 40, the specification does not adequately describe the structure required for the means for reconstitution of the composition.
The specification discloses miRNAs and EVs that are isolated from a gram-positive non-pathogenic Bacillus velezensis MTCC25513 culture, which is not representative of the entire claimed genus of any exRNA or any EV that is derived from gram-positive non-pathogenic Bacillus velezensis MTCC25513.
Additionally, not any EV of the instant genus and any exRNA or even any miRNA will result in the downregulation of any possible inflammatory gene combination. The claims are not directed to any specific type of exRNA or any specific miRNA and any specific type of EV that has been shown to result in the recited outcome of downregulation of any inflammatory gene.
In fact, depending on the miRNA, the inflammatory gene may be upregulated. For example, Das et al. (Int. J. Mol. Sci. 2022, 23, 15479, 1-27) teach various pro- and anti-inflammatory miRNAs, their targets and functions, and provides a detailed discussion on the role of miR-10a in inflammation (page 1). Das et al. is evidence that depending on the miRNA, there can be no effect on inflammation, an increase in inflammatory genes or a decrease.
Additionally, the specification does not adequately describe the genus of inflammatory genes. Without further description of the genus, one would not be able to readily envision which genes meet the instant limitation of being inflammatory.
The MPEP states that for a generic claim, the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. See MPEP § 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP § 2163. Although the MPEP does not define what constitute a sufficient number of representative species, the courts have indicated what do not constitute a representative number of species to adequately describe a broad genus. In Gostelli, the courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872, F.2d at 1012, 10 USPQ2d at 1618. Additionally, in Carnegie Mellon University v. Hoffman-La Roche Inc., Nos. 07-1266, -1267 (Fed. Cir. Sept. 8, 2008), the Federal Circuit affirmed that a claim to a genus described in functional terms was not supported by the specification’s disclosure of species that were not representative of the entire genus. Furthermore, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co. the court stated:
"A written description of an invention involving a chemical genus, like a description of a chemical species, 'requires a precise definition, such as by structure, formula, [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials." Fiers, 984 F.2d at 1171, 25 USPQ2d 1601; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284985 (CCPA 1973) ("In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus ...") Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The Guidelines for Examination of Patent Applications under the 35 USC § 112, first paragraph, “Written Description” Requirement”, published at Federal Register, Vol. 66, No. 4, pp. 1099-1111 outline the method of analysis of claims to determine whether adequate written description is present. The first step is to determine what the claim as a whole covers, i.e., discussion of the full scope of the claim. Second, the application should be fully reviewed to understand how applicant provides support for the claimed invention including each element and/or step, i.e., compare the scope of the claim with the scope of the description. Third, determine whether the applicant was in possession of the claimed invention as a whole at the time of filing.
Thus, having analyzed the claims with regard to the Written Description guidelines, it is clear that the specification does not disclose a representative number of species for exRNAs and EVs that have the required function as claimed. Thus, one skilled in the art would be led to conclude that Applicant was not in possession of the claimed invention at the time the application was filed.
Claims 32 and 38 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for delivery of specific miRNAs in a specific type of EV, each isolated from a gram-positive non-pathogenic Bacillus velezensis MTCC25513 culture, does not reasonably provide enablement for a method of treating any autoimmune disease or the listed autoimmune diseases via broad systemic delivery of any composition meeting the broad structural limitations. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Factors to be considered in a determination of lack of enablement include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)
The claims are directed to a method of treating any autoimmune disease or the listed autoimmune diseases via broad systemic delivery of any composition meeting the broad structural limitations of any exRNA that can be encapsulated in any possible EV, each being derived from gram-positive non-pathogenic Bacillus velezensis MTCC25513.
For example, rRNA can be derived from gram-positive non-pathogenic Bacillus velezensis MTCC25513 and would not meet the size constraints of many EVs. Additionally, non-vesicle rRNAs would not necessarily meet the size constraints of many EVs.
O’Brien et al. (Nature Reviews. Molecular Cell Biology, 21, 2020, 585-606) teach that the transcriptomes of different cell types are partially reflected in their extracellular vesicle RNA cargo, but the RNA profiles of extracellular vesicles differ substantially from those of their cells of origin, suggesting that some RNA species are selectively incorporated into extracellular vesicles (page 588).
O’Brien et al. teach: Small size, high abundance, ability to associate with membranes and cytoplasmic (versus nuclear) location favour incorporation of a given RNA into extracellular vesicles (page 589).
O’Brien et al. teach: Thus, many mechanisms can influence packaging of RNAs into extracellular vesicles, but the extent to which these mechanisms are specific to selected RNA species and how RNA cargo loading is regulated by the cells remain elusive (page 590).
The specification discloses miRNAs and EVs that are isolated from a gram-positive non-pathogenic Bacillus velezensis MTCC25513 culture, which is not commensurate in scope with the claimed genus of any exRNA or any EV that is derived from gram-positive non-pathogenic Bacillus velezensis MTCC25513.
Additionally, not any EV of the instant genus and any exRNA or even any miRNA will result in the downregulation of any possible inflammatory gene combination. The claims are not directed to any specific type of exRNA or any specific miRNA and any specific type of EV that has been shown to result in the recited outcome of downregulation of any inflammatory gene.
In fact, depending on the miRNA, the inflammatory gene may be upregulated. For example, Das et al. (Int. J. Mol. Sci. 2022, 23, 15479, 1-27) teach various pro- and anti-inflammatory miRNAs, their targets and functions, and provides a detailed discussion on the role of miR-10a in inflammation (page 1). Das et al. is evidence that depending on the miRNA, there can be no effect on inflammation, an increase in inflammatory genes or a decrease.
The specification does not draw an adequate nexus between delivery of the instantly recited genus of possible agents and the predictable outcome of treating any autoimmune disease or any of the recited autoimmune diseases. The claims are not limited to any specific type of exRNA. Even with regards to miRNAs, not all miRNAs will downregulate the expression of any possible inflammatory gene. Applicant has not demonstrated that any miRNA derived in any manner from gram positive non-pathogenic bacteria Bacillus velezensis MTCC25513 results in downregulation of any possible inflammatory gene.
As outlined above, it is well known that there is a high level of unpredictability in the miRNA art (a single species of the instant exRNAs) for therapeutic in vivo applications and design. The scope of the claims in view of the specification as filed together do not reconcile the unpredictability in the art to enable one of skill in the art to make and/or use the claimed invention, namely a broad method of treating any autoimmune disease via broad systemic delivery of a broad genus of agents encompassing in vivo effects.
MPEP 2164.01
Any analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention.
Also, MPEP 2164.01(a)
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
Given the teachings of the specification as discussed above, one skilled in the art could not predict a priori whether introduction of any possible exRNA and EV of the instantly recited genus in vivo by the broadly disclosed methodologies of the instantly claimed invention, would result in successful treatment of any autoimmune disease. To practice the claimed invention, one of skill in the art would have to de novo determine; the stability of the molecule in vivo, delivery of the molecule to the whole organism, specificity to the target tissue in vivo, dosage and toxicity in vivo, and entry of the molecule into the cell in vivo and the effective action therein. Without further guidance, one of skill in the art would have to practice a substantial amount of trial and error experimentation, an amount considered undue and not routine, to practice the instantly claimed invention.
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation (see MPEP 2164.01(a)).
Art of Interest
The instant claims are free of the prior art with respect specifically to the extra polymeric substances being derived from gram positive non-pathogenic bacteria Bacillus velezensis MTCC25513.
However, Goodman et al. (WO 2019/051380 A1) teach methods and compositions related to EVs useful as therapeutic agents (abstract) and teach [2] In certain aspects, provided herein are pharmaceutical compositions comprising bacterial extracellular vesicles (EVs) useful for the treatment and/or prevention of disease. These naturally occurring EVs from bacteria necessarily contain extracellular RNA.
[81] In some embodiments, the bacteria from which the EVs are obtained are modified to enhance EV production, to enhance oral delivery of the produced EVs (e.g., by improving acid resistance, muco-adherence and/or penetration and/or resistance to bile acids, digestive enzymes, resistance to anti-microbial peptides and/or antibody neutralization), to target desired cell types (e.g. M-cells, goblet cells, enterocytes, dendritic cells, macrophages), to enhance their immunomodulatory and/or therapeutic effect of the produced EVs (e.g., either alone or in combination with another therapeutic agent), and/or to enhance immune activation or suppression by the produced EVs (e.g., through modified production of polysaccharides, pili, fimbriae, adhesins).
[93] EVs obtained by methods provided herein may be further purified by size based column chromatography, by affinity chromatography, and by gradient ultracentrifugation, using methods that may include, but are not limited to, use of a sucrose gradient or Optiprep gradient. Briefly, using a sucrose gradient method, if ammonium sulfate precipitation or
ultracentrifugation were used to concentrate the filtered supernatants, pellets are resuspended in 60% sucrose, 30 mM Tris, pH 8.0. If filtration was used to concentrate the filtered supernatant, the concentrate is buffer exchanged into 60% sucrose, 30 mM Tris, pH 8.0, using an Amicon Ultra column.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Amy R Hudson whose telephone number is (571)272-0755. The examiner can normally be reached M-F 8:00am-6:00pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached at 571-270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/AMY ROSE HUDSON/Primary Examiner, Art Unit 1636
Prosecution Insights