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 .
The amendment filed 07/13/2026 has been entered. Claims 4-9, 15 and 27 have been cancelled. Claims 1-2, 10-12, 14, 16, 21, 23-24, 26, 28, 33, 35-36 and 39 have been amended. Claims 1-3, 10-14, 16-26 and 28-41 are pending and are under examination.
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 - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, 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/Rejections Withdrawn
The objection to claim 2, 12, 24, 35, 36 and 39 is withdrawn in view of the amendment to the claims.
The rejection of claims 1, 3, 10-11, 13-23, 25-34, 37-38 and 40-41 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 is withdrawn in view of the amendment to the claims.
The rejection of 15 and 27 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, is withdrawn in view of the cancellation of the claims.
The rejection of claims 10, 21 and 33 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in view of the amendment to the claims.
The rejection of claim(s) 1, 14-20, 22-23 and 26-32 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Dijk et al. US 2020/0040358 2/6/2020 is withdrawn in view of the amendment to the claims.
The rejection of claim(s) 1, 3, 11, 13, 23 and 25 is/are rejected under 35 U.S.C. 103 as being unpatentable over Dijk et al. US 2020/0040358 2/6/2020 in view of Khan et al. The Journal of Immunology, Volume 200, Issue Supplement_1, May 1 2018 is withdrawn in view of the amendment to the claims.
Claim Rejections Maintained
Claims 11-14, 16-26, 28-34 and 36-41 are 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:
for a method of therapeutically immunizing a subject against M. tuberculosis or a method of inducing an immune response to Mycobacteria tuberculosis comprising administering to the subject a formulation of recombinant adenovirus vector having a heterologous DNA segment encoding mycobacterial Ag85B-p25 epitope (SEQ ID NO: 1) or mycobacterial Ag85B-p25 epitope fusion of autophagy-inducing peptide-C5 (SEQ ID NO: 2) and enabled for the recombinant adenovirus vector encoding Ag85B-p25 epitope fusion of autophagy-inducing peptide-C5 (SEQ ID NO: 2) in infecting dendritic cells and upregulating the transcriptome of genes regulating antigen processing such as CTSA, CTSB, CTSK, CTSL, CTSS, CTSZ, Gabarap, Lgals-3, Lgals-8, LAMP1, Rab7, SQSTM1. B2M, CD53, CD63, CD68, Clec4e, H2D1, Hsp9a, LILRB4, and LAMP2;
does not reasonably provide enablement for:
a method of prophylactically immunizing a subject comprising administering to the subject a vaccine formulation of recombinant adenovirus vector having a heterologous DNA segment encoding mycobacterial Ag85B-p25 epitope (SEQ ID NO: 1), mycobacterial Ag85B-p25 epitope fusion of autophagy-inducing peptide-C5 (SEQ ID NO: 2).
a method of therapeutically immunizing a subject comprising administering to the subject a vaccine formulation of recombinant adenovirus vector having a heterologous DNA segment encoding mycobacterial Ag85B-p25 epitope (SEQ ID NO: 1), mycobacterial Ag85B-p25 epitope fusion of autophagy-inducing peptide-C5 (SEQ ID NO: 2) in general.
for a vaccine in general
For a vaccine for protection from Mycobacterium tuberculosis
An effective mucosal vaccine
An effective vaccine delivered nasally
An effective vaccine for tuberculosis
An effective vaccine for infecting dendritic cells (DC) and thereby upregulating a transcriptome of genes regulating antigen processing
An effective vaccine for infecting dendritic cells (DC) and thereby upregulating a transcriptome of genes regulating antigen processing, wherein the genes are CTSA, CTSB, CTSK, CTSL, CTSS, CTSZ, Gabarap, Lgals-3, Lgals-8, LAMP1, Rab7, SQSTM1. B2M, CD53, CD63, CD68, Clec4e, H2D1, Hsp9a, LILRB4, and LAMP2.
the replication defective bovine or human adenoviral vector encoding Ag85B-p25 epitope without the autophagy inducing peptide
upregulating transcriptome of genes regulating antigen processing in dendritic cells.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(A)). These include nature of the invention, breadth of the claims, guidance of the specification, the existence of working examples, state of the art, predictability of the art and the amount of experimentation necessary. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the Invention
The claims are drawn to:
A method of therapeutically or prophylactically immunizing a subject comprising administering to the subject a vaccine formulation of a recombinant adenovirus vector having a heterologous DNA segment encoding mycobacterial Ag85B-p25 epitope (SEQ ID NO: 1), mycobacterial Ag85B-p25 epitope fusion of autophagy-inducing peptide-C5 (SEQ ID NO: 2).
The claims are also drawn to a pharmaceutical composition for therapeutically or prophylactically immunizing a subject comprising a recombinant adenovirus vector having a heterologous DNA segment encoding mycobacterial Ag85B-p25 epitope (SEQ ID NO: 1), mycobacterial Ag85B- p25 epitope fusion of autophagy-inducing peptide-C5 (SEQ ID NO: 2), together with one or more pharmaceutically acceptable carriers, diluents, or excipients.
Breadth of the Claims
The invention as claimed is very broad in scope. This is because the claims require the therapeutically or prophylactically immunizing a subject generally and not limited to a particular pathogen and/or disease.
Guidance in the Specification/The Existence of Working Examples
The specification discloses a gene cassette of the Ag85B-p25 epitope of Mycobacterium tuberculosis without or with the autophagy-inducing peptide C5 (AIP-C5). The gene cassette was cloned into replication defective bovine adenovirus vector and replication defective human adenovirus vector. See Figure 1A and paragraph 9.
The specification teaches that replication defective bovine adenovirus vector expressing the 85B epitope and the AIP-C5 (BAdv85C5) and human adenovirus vector expressing the 85B epitope and the AIP-C5 (HAdv85C5) induces transcription of genes in mouse dendritic cells. See paragraph 10 and 80.
Upregulation a transcriptome of genes regulating antigen processing:
The specification disclose BAdv85C5 better upregulated the expression of CTSB, CTSA, CTSS, CTSK, CTSZ in dendritic cells compared to HAdv85C5. BAdv85C5 and HAdv85C5 also upregulated the expression of H2D1, B2M, HSPA9A, CD68, Gabarap, SQSTM1 RAB7 and L-gals-3 albeit at different levels.
The specification does not teach that the replication defective bovine or human adenoviral vector encoding Ag85B-p25 epitope alone without the autophagy inducing C5 peptide upregulated the expression of these genes in dendritic cells. Thus, it appears that the C5 peptide is necessary in addition to the Ag85B-p25 epitope in the context of the bovine or human adenoviral vector for upregulating a transcriptome of genes regulating antigen processing, wherein the genes are CTSA, CTSB, CTSK, CTSL, CTSS, CTSZ, Gabarap, Lgals-3, Lgals-8, LAMP1, Rab7, SQSTM1. B2M, CD53, CD63, CD68, Clec4e, H2D1, Hsp9a, LILRB4, and LAMP2.
Vaccine, therapeutically immunizing a subject and prophylactically immunizing a subject:
The specification teaches that BAdv85C5 and BAdv85 induced immune responses that reduced the M. tuberculosis microbial counts in different organs such as the spleen, lungs in an M. tuberculosis. See Figure 6C.
The specification does not correlate immune response generated by a recombinant adenovirus vector encoding Ag85B-p25 fusion or encoding Ag85B-p25-autophagy-inducing peptide-C5 fusion with treating or prophylactically immunizing as an effective vaccine protection from any other microorganism including other Mycobacterium species.
There is no evidence that the recombinant adenovirus vector encoding M. tuberculosis antigens is therapeutically or prophylactically immunizes a subject generally against other microbes or other mycobacteria species.
Thus, it can be concluded that the recombinant adenovirus vector encoding the M. tuberculosis antigens reduced M. tuberculosis infection in lung and spleen in a M. tuberculosis challenge model but did not prevent the infection.
State of the Art and Predictability of the Art and Amount of experimentation Necessary
There are uncountable microorganisms and diseases thereof and the type of immune responses required to treat or prevent infection/diseases from one microorganism may not apply to another microorganism. The state of the vaccine art is very complex.
Using HBV virus as an example to demonstrate the complexity of developing vaccines, the art teaches that HBV therapeutic vaccines clear HBV infection but do not prevent the infection of a person. For example, Chuai et al (PLOS One, 8 (1): e54126, 2013) disclose that the currently used commercially available HBV vaccine combined with alum adjuvant, does not stimulate robust Th1 immunity or enhance the CTL responses that are critical to virus clearance during acute or chronic HBV infection. See p. 2 second column last paragraph to p. 2 first column and first paragraph. Prophylactic vaccines only need to provoke neutralizing antibodies directed against the HBV envelop proteins, whereas therapeutic vaccines are most likely needed to induce a comprehensive T cell response and thus, should include other HBV antigens, such as HBV core and polymerase. See abstract of Mahmood et al. Vaccines (Basel) 2023 Dec 18;11(12):1862.
There is no evidence that the claimed recombinant adenovirus vector encoding M. tuberculosis antigens can generate the immune responses required for a therapeutic or prophylactic vaccine against any other microbe.
Regarding, Mycobacteria including Mycobacteria tuberculosis, the prevention of M. tuberculosis infection and tuberculosis disease is complex.
The sole licensed TB vaccine to date is Bacille Calmette-Guérin (BCG), which was first developed in 1921 and is still widely used throughout the world. BCG provides significant protection against disseminated and meningeal TB when administered soon after birth, and protection lasts for up to 10 years. However, BCG’s efficacy against pulmonary TB in adults and adolescents varies greatly and has proven variable in its ability to reduce the incidence of pulmonary TB. Most subunit TB vaccines target certain proteins from M. tuberculosis and as such the breadth of immune response is generally much narrower, which makes the choice of antigenic target particularly important. viruses (i.e., the vector) are engineered to encode genes for M. tuberculosis proteins.
After immunization with the viral particles, virally infected cells are turned into factories to produce the M. tuberculosis proteins and induce a robust immune response without the need of an exogenous adjuvant. This approach leverages decades of experience using attenuated viruses as vaccines (e.g., poliovirus, vaccinia, measles) and takes advantage of the immune system’s strong innate and adaptive immune responses to viruses. One major downside to the use of viral vectors is the existence of pre-existing immunity to the virus. If a person has preexisting immunity to the vector at the time of vaccination, immune responses to the vector will be boosted, leading to premature clearing of the virus and dampening of the M. tuberculosis-specific response. To circumvent this potential problem, vaccine developers are using rare human serotypes (e.g., AdHu35) or viruses from other species (e.g., ChAd68Ag85A and ChAdOx1.85A). See Lai et al. pj Vaccines 8, 158 (2023). https://doi.org/10.1038/s41541-023-00750-7.
The nature of the instant invention is broad and complex for at least the reasons stated above, and it would require “undue experimentation” to provide for a vaccine, therapeutically or prophylactically immunize a subject generally i.e. against any microorganism.
The instant specification has not taught how to use the instant invention commensurate with the scope of the claims.
The ability of the claimed recombinant adenovirus vector encoding M. tuberculosis antigens in treating and preventing infection from any microorganism is unpredictable especially because of the differences in the pathogenicity of each microorganism and the differences in the immune responses needed to treat or prevent infection from each microorganism.
"The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art." "The "amount of guidance or direction" refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling". Physiological activity can be considered inherently unpredictable. Thus, Applicant assumes a certain burden in establishing that inventions involving physiological activity are enabled. See MPEP 2164.03.
It is determined that the specification does not reasonably provide enablement for:
a method of prophylactically immunizing a subject comprising administering to the subject a vaccine formulation of recombinant adenovirus vector having a heterologous DNA segment encoding mycobacterial Ag85B-p25 epitope (SEQ ID NO: 1), mycobacterial Ag85B-p25 epitope fusion of autophagy-inducing peptide-C5 (SEQ ID NO: 2);
a method of therapeutically immunizing a subject comprising administering to the subject a vaccine formulation of recombinant adenovirus vector having a heterologous DNA segment encoding mycobacterial Ag85B-p25 epitope (SEQ ID NO: 1), mycobacterial Ag85B-p25 epitope fusion of autophagy-inducing peptide-C5 (SEQ ID NO: 2) in general;
for a vaccine in general;
For a vaccine for protection from Mycobacterium tuberculosis;
An effective mucosal vaccine;
An effective vaccine delivered nasally;
An effective vaccine for tuberculosis;
An effective vaccine for infecting dendritic cells (DC) and thereby upregulating a transcriptome of genes regulating antigen processing;
An effective vaccine for infecting dendritic cells (DC) and thereby upregulating a transcriptome of genes regulating antigen processing, wherein the genes are CTSA, CTSB, CTSK, CTSL, CTSS, CTSZ, Gabarap, Lgals-3, Lgals-8, LAMP1, Rab7, SQSTM1. B2M, CD53, CD63, CD68, Clec4e, H2D1, Hsp9a, LILRB4, and LAMP2; and
the replication defective bovine or human adenoviral vector encoding Ag85B-p25 epitope without the autophagy inducing peptide upregulating transcriptome of genes regulating antigen processing in dendritic cells.
The specification is enabling for a method of therapeutically immunizing a subject against M. tuberculosis or a method of inducing an immune response to Mycobacteria tuberculosis comprising administering to the subject a formulation of recombinant adenovirus vector having a heterologous DNA segment encoding mycobacterial Ag85B-p25 epitope (SEQ ID NO: 1) or mycobacterial Ag85B-p25 epitope fusion of autophagy-inducing peptide-C5 (SEQ ID NO: 2) and enabled for the recombinant adenovirus vector encoding Ag85B-p25 epitope fusion of autophagy-inducing peptide-C5 (SEQ ID NO: 2) in infecting dendritic cells and upregulating the transcriptome of genes regulating antigen processing such as CTSA, CTSB, CTSK, CTSL, CTSS, CTSZ, Gabarap, Lgals-3, Lgals-8, LAMP1, Rab7, SQSTM1. B2M, CD53, CD63, CD68, Clec4e, H2D1, Hsp9a, LILRB4, and LAMP2.
Response to Applicants’ Argument
Applicant state that the claim have been amended to the context of treatment of infection by mycobacteria, including infection by Mycobacterium tuberculosis.
Applicants’ argument has been carefully considered but is not found persuasive. The claims are not limited to mycobacteria, including infection by Mycobacterium tuberculosis. In addition, the specification is not enabled for vaccines for other Mycobacteria species or therapeutically or prophylactically immunizing against other Mycobacteria species or other microbes in general. The scope of claim 11, 23, for example, is not limited to mycobacteria or Mycobacterium tuberculosis. The specification teaches that BAdv85C5 and BAdv85 induced immune responses that reduced the M. tuberculosis microbial counts in different organs such as the spleen, lungs in an M. tuberculosis. See Figure 6C. Thus, the BAdv85C5 and BAdv85 did not prevent infection but reduced the challenge burden in the immunized animals. Thus, the claims are not enabled for a “vaccine” or prophylactic immunization regarding Mycobacteria and Mycobacteria tuberculosis and any other microbe. For these reasons and as set forth in the rejection, the rejection is maintained.
New Claim Rejection Based on Amendment
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 2, 12, 24, 35, 36, 39 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.
The metes and bounds of the claims is vague and indefinite because the claims recite “the amino acid sequence set forth in SEQ ID NO: 3” and “the amino acid sequence set forth in SEQ ID NO: 3”, however SEQ ID NO:3 and SEQ ID NO: 4 are nucleic acid sequences.
Status of Claims
Claims 2, 11-14, 16-26 and 28-41 are rejected. Claim 1, 3 and 10 are allowed.
Applicants’ 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).
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/OLUWATOSIN A OGUNBIYI/Primary Examiner, Art Unit 1645
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