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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on November 15, 205 has been considered by the examiner.
Claim Objections
Claim 5 is objected to because of the following informalities: Line 5 recites, “LPS”. Acronyms should be spelled out prior to first use. 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.
Claim 5 is 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.
Claim 5 requires that the bacterium comprises a mutation, the mutation is:
a gain of function that enhances immunogenicity comprising expression of a molecule that interacts with a Toll- like receptor. a phagocyte, or a lymphocyte;
is a loss of function mutation in genes that encode for products that mediate reactogenicity comprising LPS synthesis;
is deletion of genes that blunt the immune response comprising antiphaqocytic proteins;
is directed to multiple mutations in several genes that affect the immune response or the presentation of antigens in or on the bacteria; or
said mutation is directed to large scale mutations or deletions such that the bacteria have a substantially reduced set of genes, up to the limits of bacterial cell viability mutations reduced set of genes “up to the limits of cell viability”.
However, since the bacterial cell is killed in claim 1, from which claim 5 depends it is not viable.
Regarding the previous rejection of claim 5, applicant points to page 34, line 30 through page 35, line 5, where the claim language is supported with exemplative discussions of toll-like receptors (TLR) and other ways that enhance interactions with phagocytes and lymphocytes, antiphagocytic proteins that blunt the immune response, and TLR agonists. Applicant also points to working examples 1-4, exemplifying HIV MPER expressed on the surface of killed whole cell bacteria.
The instant claim amendments, page 34, line 30 to page 35, line 5, and working examples 1-4 have been fully considered, but are found unpersuasive. Example 4 exemplifies HIV MPER expressed on the surfaces of Killed Whole Cell (KWC) bacteria. However, there is no indication that the mutations recited in claim 5, described on page 34, line 30 to page 35, line 5, are made in killed whole cell bacterium or a minicell, as required. Genetic structures correlating the activities and functions in a KWC bacteria and/or a minicell, as required, cannot be found. There is no teaching for which genes are mutated that result in affecting the immune response, either by enhancement or blunting. There is no teaching for which genes are mutated that result in affecting the presentation of antigens in or on the KWC bacteria or the minicell. It cannot be determined whether the multiple mutations in the bacteria intended to increase or decrease presentation of antigens in or on the bacteria, “is directed to large scale mutations or deletions such that the bacteria have a substantially reduced set of genes, up to the limits of bacterial cell viability.” The instant specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of any specific mutation(s)/ deletion(s) required to achieve the asserted functions in a KWC or minicell. One of ordinary skill in the art would not be reasonably apprised of the scope of the invention, recited in claim 5.
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.
Claim 5 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(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. This is a new matter rejection.
Claim 5 requires that the bacterium comprises a mutation, the mutation is:
a gain of function that enhances immunogenicity comprising expression of a molecule that interacts with a Toll- like receptor. a phagocyte, or a lymphocyte;
is a loss of function mutation in genes that encode for products that mediate reactogenicity comprising LPS synthesis;
is deletion of genes that blunt the immune response comprising antiphaqocytic proteins;
is directed to multiple mutations in several genes that affect the immune response or the presentation of antigens in or on the bacteria; or
said mutation is directed to large scale mutations or deletions such that the bacteria have a substantially reduced set of genes, up to the limits of bacterial cell viability mutations reduced set of genes “up to the limits of cell viability”.
However, since the bacterial cell is killed in claim 1, from which claim 5 depends it is not viable. There is no indication that the mutations recited in claim 5, described on page 34, line 30 to page 35, line 5, are made in KWC bacteria or a minicell, as required. Genetic structures correlating the activities and functions recited in claim 5, in a KWC bacteria and/or a minicell, cannot be found. There is no teaching for which genes are mutated that result in affecting the immune response, either by enhancement or blunting. There is no teaching for which genes are mutated that result in affecting the presentation of antigens in or on the KWC bacteria or the minicell. Applicant is requested to point out where support can be found.
In reply to the written description rejection of record, applicant points to page 34, line 30 through page 35, line 5, where the claim language is supported with exemplative discussions of toll-like receptors (TLR) and other ways that enhance interactions with phagocytes and lymphocytes, antiphagocytic proteins that blunt the immune response, and TLR agonists. Applicant also points to working examples 1-4, exemplifying HIV MPER expressed on the surface of killed whole cell bacteria.
The excerpts pointed to by applicant in the instant published disclosure have been fully considered, but are found unpersuasive. Structures correlating the activities and functions recited in the claim, cannot be found. There is no requisite means of comparison described in the instant disclosure for which gene(s) correspond to the requisite phenomenon of enhancement of immunogenicity comprising “expression of a molecule” that interacts with a Toll-like receptor, a phagocyte, or a lymphocyte; or a loss of function “mutation in genes that mediate reactogenicity comprising LPS synthesis”; “deletion of genes that blunt the immune response comprising antiphagocytic proteins”;…”multiple mutations in several genes that affect any immune response or affect the presentation of antigens in or on the (KWC) bacteria surface (or minicell); or substantial reduction of bacterial gene expression, “up to the limits of bacterial cell viability” in a KWC bacteria or minicell, as required. There is no description provided in the instant disclosure for KWC bacterial or minicell mutation(s) that result in the attributes recited. One skilled in the art cannot, as one can do with a fully described genus, visualize or recognize the identity of the members of bacterial mutation(s) that result in the function(s) recited. A definition by function alone "does not suffice, to sufficiently describe a coding sequence "because it is only an indication of what the gene does, rather than what it is." Eli Lily, 119 F.3 at 1568, 43 USPQ2d at 1406. The instant specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of any specific mutation(s)/ deletion(s) required to achieve the asserted functions, especially since some of the desired functions recited contradict other desired functions recited. One of ordinary skill in the art would not be reasonably apprised of the scope of the invention, recited in claim 5.
The applicable standard for the written description requirement can be found in MPEP 2163; University of California v. Eli Lilly, 43 USPQ2d 1398 at 1407; PTO Written Description Guidelines; Enzo Biochem Inc. V. Gen-Probe Inc., 63 USPQ2d 1609; Vas- Cath Inc. v. Mahurkar, 19 USPQ2d 1111; and University of Rochester V. G.D. Searle & Co., 69 USPQ2d 1886 (CAFC 2004). To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. In this case, Example 4 describes a KWC Salmonella influenzae expressing an AIDA-AT expression cassette that expresses HIV MPER on the surface. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed subject matter. The court clearly states in Vas-Cath Inc. V. Mahurkar, 19 USPQ2d 1111, that "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 page 1117.) The specification does not clearly allow persons of ordinary skill in the art to recognize that the inventors invented what is claimed. As discussed above, the skilled artisan cannot envision the distinguishing, identifying characteristics of the encompassed by the subject matter claimed.
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.
Claims 1-5, 7-9, 14, 16-18, 20-22, 24, 27, 29, 31, and 37 are rejected under 35 U.S.C. 103 as being unpatentable over Giacalone et al. (USPgPub 2010/0112670) and Zeichner (USPgPub 2010/0152059), of record.
Giacalone et al. teach a minicell to display heterologous proteins on the surface for administered targeted delivery, see paragraph [0008, 0009, 0012, 0028-0030 and 0035], as required by instant claim 1. Paragraphs [0107-0108] describe pharmaceutically acceptable carriers, recited in instant claims 14 and 37, and paragraph [013] teaches administration by oral, rectal, nasally, and parenterally, recited in instant claim 17. Paragraphs [0035-0037, 0041, and 0114] teach that the minicells displaying polypeptides stimulate cellular and humoral (antibody) immune responses against one or more viral antigens, as required by instant claims 9, 16, 18, 20-22, and 24. Paragraph [0040] states:
…minicells are genetically "engineered" to express and display recombinant targeting proteins on their surfaces. This has been successfully accomplished in Salmonella enterica by using fusion proteins that contain an Antigen 43-.alpha. outer membrane anchoring domain fused to a single chain Fv (scFv) antibody fragment with specificity for Chlam 12 or CTP3. In a similar study, E. coli cells expressing and displaying single chain Fv antibody fragments directed towards Coronavirus epitopes fused with the outer membrane localized IgA protease of Neisseria gonorhoeae were shown to neutralize Coronavirus and prevent infection in vitro. The same types of strategies could be employed to generate and display targeted fusion proteins on the surfaces of minicells…Enterobacteriaceae or Bacillaceae family member such that said minicells become "specific" targeted delivery vehicles for antigens present on the surface of cell, tissue, or organ types involved in various clinical indications. Achieving this goal is a matter of creating a nucleic acid sequence encoding for a fusion protein between a putative or predicted outer membrane protein or outer membrane localization sequence.
Also see paragraphs [0088, 0099, 0100, 0101]. The minicell-producing bacteria are derived from Salmonella and E. coli, see paragraph [0010], as required by instant claims 2-4. Paragraphs [0030-0034] of Gacolone et al. describe introduction of a multifunctional suicide mechanism (MSM) that functions to kill chromosome-bearing parental cells (Killed Whole Cells) to improve safety profiles of the minicell preparations. Paragraphs [0103-0105] describe reducing pyrogenicity and toxicity of the minicell by eliminating the msbB gene parental minicell-producing strains producing lipopolysaccharide (LPS), as (the intended meaning?) in claim 5.
Paragraphs [0052 and 0053] of Giacalone et al. describe inducible promoters, recited in claim 31. Paragraphs [0088 and 0089] describe creating a nucleic acid encoding a fusion protein comprising polypeptide of interest and an outer membrane localization sequence of the “autotransporter” family. However, Giacalone et al. do not mention a trimeric Haemophilus influenzae (Hia) autotransporter expression vector, recited in claims 1, 7, 8, 27, and 29.
Zeichner discusses the trimeric H. influenzae autotransporter expression vector in paragraphs [0034 and 0063].
One of ordinary skill in the art prior to the effective filing date would have been motivated to have used the trimeric H. influenzae autotransporter expression vector as the nucleic acid encoding the heterologous antigen expressed on minicell surfaces of Giacalone et al. because Zeichner teaches that the trimeric H. influenzae autotransporter expression vector naturally transports and expresses proteins on the membrane surfaces as multimers, facilitating protein folding into structures resembling natural conformations in paragraphs [0034 and 0063]. One of ordinary skill in the art prior to the effective filing date would have had a reasonable expectation of success to have used the trimeric H. influenzae autotransporter expression vector of Zeichner as the nucleic acid encoding the heterologous antigen expressed on minicell surfaces of Giacalone et al. because both Giacalone et al. and Zeichner teach using a nucleic acid to express a heterologous protein under the control of an inducible promoter on the membrane surface of a minicell, see paragraphs [0008, 0009, 0012, 0028-0030, 0035-0037, 0040, 0041,0052, 0053, 0088, 0099, 0100, 0101, and 0114] of Giacalone et al. and the membrane surface of a Gram-negative bacterium in paragraphs [0023, 0024, 0033, 0034, 0036, and 0063] of Zeichner.
Claims 10, 11, 19, 23, 26, 33, 41, 43, and 44 are rejected under 35 U.S.C. 103 as being unpatentable over Giacalone et al. and Zeichner as applied to claims 1-5, 7-9, 14, 16-18, 20-22, 24, 27, 29, 31, and 37 above, and further in view of Krebs et al. (PLoS ONE. 2014: 16; 9 (12): e113463), and further in view of any of the following alignments in the alternative (all previously of record):
Geneseq db access no AZG77045 in WO2011038290 by Mascola et al. 2011 shares 100% identity with instant SEQ ID NO: 7, see the alignment provided; or
Geneseq db access no BEG89323 in WO2017143062 by Kyratsous et al. 2017 shares 100% identity with instant SEQ ID NO: 9, see the alignment provided; or
Geneseq db access no AXV62568 in WO2010019262 by Fischer et al. 2010 shares 100% identity with instant SEQ ID NO: 10, see the alignment provided.
See the teachings of Giacalone et al. and Zeichner above. While Giacalone et al. teach the heterologous antigen is from a virus in paragraph [0036] and discusses prevention and neutralization of coronavirus infection when coronavirus epitopes are fused to the outer membrane localized IgA protease of Neisseria gonorhoeae in paragraphs [0040 and 0088], Giacalone et al. do not teach or suggest the antigen is an HIV membrane-proximal external region (MPER) peptide, recited in claims 10, 11, 33, or inducing neutralizing antibodies against the peptide, recited in claims 19, or administering the composition to a subject infected with HIV, recited in instant claim 26, or the MPER peptide comprising SEQ ID NOs: 7, 9 or 10, recited in claim 41; or a purified MPER and a modified bacterium recited in claim 43, where the MPER antigen is linked to the surface of the bacterium, recited in claim 44.
Krebs et al. teach inducing HIV MPER-specific antibodies and cross-neutralization antibodies that is a target during infection, see the abstract, Introduction, and Figures 2-4, 6 and 7. The HIV MPER monomer of Krebs et al. is linked to the 5’ end of the E2 protein of Geobacillus stearothermophilus, see the abstract and Figure 1.
One of ordinary skill in the art prior to the effective filing date would have been motivated to have expressed Geneseq db access no AZG77045 in WO2011038290 by Mascola; or Geneseq db access no BEG89323 in WO2017143062 by Kyratsous et al. or Geneseq db access no AXV62568 in WO2010019262 by Fischer et al. as the heterologous antigen expressed on the minicell surface of Giacalone et al. to induce an immune response against the HIV gp41 MPER peptide, as taught by Krebs et al. One of ordinary skill in the art prior to the effective filing date would have had a reasonable expectation of success for expressing the Geneseq db access no AZG77045 in WO2011038290 by Mascola; or Geneseq db access no BEG89323 in WO2017143062 by Kyratsous et al. or Geneseq db access no AXV62568 in WO2010019262 by Fischer et al. as the heterologous antigen expressed on the minicell surface of Giacalone et al. because Giacalone et al. teach expressing any heterologous antigen on a minicell surface, see paragraphs [0008, 0009, 0012, 0028, 0029, 0035-0037, 0040, 0041, 0088, 0089, 0099, and 0114].
Allowable Subject Matter
Claims 42 and 45-48 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. The prior art does not teach or suggest SEQ ID NOs: 5, 6, and 11-13 or a homolog sharing at least 95% identity thereto, as required.
Conclusion
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SHANON A FOLEY whose telephone number is (571)272-0898. The examiner can normally be reached M-F, generally 5:30 AM-5 PM, flexible.
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/Shanon A. Foley/Primary Examiner, Art Unit 1671