The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Election/Restrictions
Applicant’s election without traverse of Group I in the reply filed on 5-28-2025 is acknowledged. Claims 13-30 are pending. Claims 26-30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 13-25 are currently under examination.
Information Disclosure Statement
The Information Disclosure Statement filed on 1-5-2023 has been considered. An initialed copy is attached hereto.
It should be noted that the listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Objections
Claim 21 is objected to for utilizing the abbreviation for the genus name “Enterococcus” without defining it upon its first recitation.
Claim 22 is objected to for utilizing the abbreviation for the genus name “Enterococcus” without defining it upon its first recitation.
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.
Deposit Requirement
Claim 22 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
It is apparent that the bacterial strains E. faecium LMG 15710, E. faecium NCIMB 10415 (SF68), E. faecium W54, E. faecium LMG S-28935 and E. faecium THT020101 are required in order to practice the invention. The deposit of biological organisms is considered by the Examiner to be necessary for the enablement of the current invention (see 37 CRF 1.808(a)). The examiner acknowledges the deposit of organisms under the ATCC accession numbers VR-2649, VR-2653, VR-2647 and VR2652 in partial compliance with this requirement. However, said deposits are not in full compliance with 37 CFR 1.803-1.809.
If the deposit is made under terms of the Budapest Treaty, then an affidavit or declaration by Applicants or person(s) associated with the patent owner (assignee) who is in a position to make such assurances, or a statement by an attorney of record over his or her signature, stating that the deposit has been made under the terms of the Budapest Treaty and that all restrictions imposed by the depositor on the availability to the public of the deposited material will be irrevocably removed upon the granting of a patent, would satisfy the deposit requirements. See 37 CFR 1.808.
If a deposit is not made under the terms of the Budapest Treaty, then an affidavit, or declaration by Applicants or person(s) associated with the patent owner (assignee) who is in a position to make such assurances, or a statement by an attorney of record over his or her signature, stating that the following criteria have been met:
1) during the pendency of the application, access to the deposit will be afforded to one determined by the Commissioner to be entitled thereto;
2) all restrictions imposed by the depositor on the availability to the public of the deposited material will be irrevocably removed upon the granting of a patent; and
3) the deposits will be maintained for a term of at least thirty (30) years from the date of the deposit or for the enforceable life of the patent or for a period of at least five (5) years after the most recent request for the furnishing of a sample of the deposited material, whichever is longest; and
4) a viability statement in accordance with the provisions of 37 CFR 1.807; and
5) the deposit will be replaced should it become necessary due to inviability, contamination or loss of capability to function in the manner described in the specification.
In addition, the identifying information set forth in 37 CRF 1.809(d) should be added to the specification. See 37 CFR 1.803 – 1.809 for additional explanation of these requirements.
Written Description
Claims 13-25 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 rejected claims are drawn to methods of reducing metastasis of any and all forms of colorectal cancer utilizing a microorganism that reduces or blocks activity of a pro-metastatic quorum-sensing peptide or a metabolite thereof present in a gastrointestinal tract or blood of the subject; and/or that reduces or blocks production of the pro-metastatic quorum-sensing peptide or the metabolite thereof in the gastrointestinal tract or blood of the subject. The claims optionally require:
the pro-metastatic quorum- sensing peptide comprises EntF (SEQ ID NO:2) or the metabolite EntF* (SEQ ID NO: 1) of EntF (claim 14);
the microorganism is selected from the group consisting of engineered microorganisms and bacterial strains, wherein the engineered microorganisms are unable to synthesize pro-metastatic quorum sensing peptides, and/or the engineered microorganisms reduce or inhibit functionality of the pro-metastatic quorum-sensing peptide or the metabolite; and the bacterial strains are unable to synthesize the pro-metastatic quorum sensing peptide (claim 15);
the microorganism comprises engineered bacteria, wherein: the engineered bacteria are unable to synthesize pro-metastatic quorum sensing peptides; and/or the engineered bacteria reduce or inhibit functionality of the pro-metastatic quorum- sensing peptide or the metabolite (claim 16);
the microorganism comprises bacterial strains that are unable to synthesize the pro-metastatic quorum sensing peptide and are able to reduce or inhibit the production of the pro-metastatic quorum-sensing peptide by gut microbiota (claim 17);
the microorganism is a bacterial strain that does not produce EntF*; or the microorganism is a bacterial strain that lacks EntF genes (claim 18);
the microorganism is a bacterial strain from order Lactobacillales (claim 19);
the bacterial strain is from genus Enterococcus or genus Lactococcus (claim 20);
the bacterial strain is E. faecium that is free of EntF and EntF* as determined by at least one of qPCR or UHPLC-MS/MS (claim 21);
the bacterial strain is the bacterial strains E. faecium LMG 15710, E. faecium NCIMB 10415 (SF68), E. faecium W54, E. faecium LMG S-28935 or E. faecium THT020101 (claim 22);
the microorganism is a bacterial strain that does not produce EntF*; and the bacterial strain reduces production of EntF* by other bacterial strains in the gastrointestinal tract of the subject by altering bacterial flora and/or by suppressing levels of bacterial strains that produce EntF/EntF* (claim 23); and/or
the bacterial strain reduces or prevents a presence of bacterial strains producing EntF*.
Consequently, the instant claims encompass the use of a myriad microorganisms with differing combinations endogenous and heterologous sequences. People of skill in the art require evidence that a benefit can be derived by the application of a given substance(s). The specification, as filed, is limited to the determining the effect of Entf* on tumor growth but is silent with regard to the use of any microorganism encompassed by the rejected claims to reduce the metastasis of any type of colorectal cancer Moreover, while the specification shows the effects of Entf* on tumor growth, it is silent with regard to the doses, mode of administration and dosing regimen needed to reduce the metastasis of a given colorectal cancer lymphoma when utilizing a given microorganism encompassed by the rejected claims. Applicant describes the use of the aforementioned microorganisms in a generalized and prophetic sense but fails to demonstrate the therapeutic efficacy of any microorganism with the claimed genotype/phenotype comprising any of the claimed combinations of heterologous genes in any animal system. While the skill in the art of immunology is high, to date, prediction of a therapeutic effect for any given composition in any given animal is quite unpredictable. Given the lack of success in the art, the lack of working examples and the unpredictability of the generation of a directed immune response, none of the claimed “therapeutic compositions” meet the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. The specification provides insufficient written description to support the genus encompassed by the claim.
To fulfill the written description requirements set forth under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, the specification must describe at least a substantial number of the members of the claimed genus, or alternatively describe a representative member of the claimed genus, which shares a particularly defining feature common to at least a substantial number of the members of the claimed genus, which would enable the skilled artisan to immediately recognize and distinguish its members from others, so as to reasonably convey to the skilled artisan that Applicant has possession the claimed invention. To adequately describe the genus of cancer therapeutics, Applicant must adequately describe which microorganisms reduces or blocks activity of a pro-metastatic quorum-sensing peptide or a metabolite thereof present in a gastrointestinal tract or blood of the subject; and/or that reduces or blocks production of the pro-metastatic quorum-sensing peptide or the metabolite thereof in the gastrointestinal tract or blood of the subject. Moreover, Applicant must describe the means by which said therapeutic is to be administered in order to have efficacy in treating a given melanoma or lymphoma. The specification, however, does not disclose distinguishing and identifying features of a representative number of members of the genus of therapeutics to which the claims are drawn, such as a correlation between the genotype/phenotype of a given microorganism and its recited function (reducing the metastasis of a given colorectal cancer), so that the skilled artisan could immediately envision, or recognize at least a substantial number of members of the claimed genus of therapeutics. Therefore, the specification fails to adequately describe at least a substantial number of members of the genus of therapeutics to which the claims refer. The specification discloses the use of Entf* on tumor growth but does not provide any basis for correlating the in vitro and xenograft results with beneficial effects that could reasonably be expected when a microorganism encompassed by the instant claims is administered in vivo to reduce the metastasis of colorectal cancers Lacking either direct evidence for in vivo benefit, or a reasonable basis for correlating the in vitro and xenograft data (as exemplified in the instant specification) with in vivo benefit, the specification cannot be said to disclose how to use the claimed microorganisms as pharmaceuticals (i.e. therapeutic) without undue trial and error. Moreover, while those of skill in the art recognize that in vitro assays and or cell-cultured based assays are somewhat useful to observe basic physiological and cellular phenomenon such as screening the effects of potential drugs, clinical correlations are generally lacking. The greatly increased complexity of the in vivo environment as compared to the very narrowly defined and controlled conditions of an in vitro assay does not permit a single extrapolation of in vitro assays to in vivo efficacy with any reasonable degree of predictability. In vitro assays cannot easily assess cell-cell interactions that may be important in a particular pathological state. Furthermore it is well known in the art that cultured cells, over a period time, lose phenotypic characteristics associated with their normal counterpart cell type.
As set forth supra, the specification fails to describe any microorganism generally or Enterococcus faecium specifically that has efficacy in reducing the metastasis of any type of colorectal cancer therefore does not disclose the diverse genus of therapeutics encompassed by the rejected claims.
To fulfill the written description requirements set forth under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, the specification must describe at least a substantial number of the members of the claimed genus, or alternatively describe a representative member of the claimed genus, which shares a particularly defining feature common to at least a substantial number of the members of the claimed genus, which would enable the skilled artisan to immediately recognize and distinguish its members from others, so as to reasonably convey to the skilled artisan that Applicant has possession the claimed invention. To adequately describe the genus of therapeutics, Applicant must adequately describe a structure/function correlation ( i.e. demonstration of which of microorganism with the claimed genotypical/phenotypical characteristics, if any, has efficacy in reducing the metastasis of a given colorectal cancer) OR showing a number of species that are representative of the breadth of the genus. However, the present specification fails to show any of the recited microorganisms as having any therapeutic function against any type of colorectal.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed' ”. The courts have decided:
The purpose of the “written description” requirement is broader than to merely explain how to “make and use”; the 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, whatever is now claimed.
See Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991). Furthermore, the written description provision of 35 USC § 112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
MPEP 2163.02 further states, “[p]ossession may be shown in a variety of ways including description of an actual reduction to practice, or by showing the invention was 'ready for patenting' such as by disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention” See, e.g., Pfaff v. Wells Elecs., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641, 1647 (1998); Regents of the Univ. of Cal. v. Eli Lilly, 119 F.3d 1559, 1568, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997); Amgen, Inc. v. Chugai Pharm., 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) (one must define a compound by "whatever characteristics sufficiently distinguish it"). Moreover, because the claims encompass a genus of variant species, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed.
Additionally, MPEP 2163 states:
"A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004)”
And:
For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation." Such correlations may be established "by the inventor as described in the specification," or they may be "known in the art at the time of the filing date." See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014) (Holding that claims to all human antibodies that bind IL-12 with a particular binding affinity rate constant (i.e., koff) were not adequately supported by a specification describing only a single type of human antibody having the claimed features because the disclosed antibody was not representative of other types of antibodies in the claimed genus, as demonstrated by the fact that other disclosed antibodies had different types of heavy and light chains, and shared only a 50% sequence similarity in their variable regions with the disclosed antibodies.).
Therefore, because the art is unpredictable, in accordance with the MPEP and currently case law, the description of claimed vaccines/therapeutics is not deemed representative of the genus of microorganisms to which the claims refer.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ROBERT A ZEMAN whose telephone number is (571)272-0866. The examiner can normally be reached Monday thru Friday; 6:30 am - 3pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gary B Nickol can be reached at 571-272-0835. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ROBERT A ZEMAN/Primary Examiner, Art Unit 1645 August 23, 2025
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