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 04/23/2026 has been entered. Claims 2-20, 22-25, 40 and 45 have been cancelled. Claims 1, 21, 26-39 and 41-44 are pending and under examination.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, 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 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 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”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 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 statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - The incorporation by reference paragraph required by 37 CFR 1.834(c)(1), 1.835(a)(2), or 1.835(b)(2) is defective because the size of the XML file should be in bytes instead of kilobytes.
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 Rejections Withdrawn
The rejection of claim 2-3 on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 9084749 (‘749) is withdrawn in view of the cancellation of the claims.
The rejection of claims 1, 3 and 21 on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 10,525,118 (‘118) is withdrawn in view of the amendment to the claims.
The rejection of claims 1-2, 22-31 and 33-45 on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 10,525,118 (‘118) as applied to claims in view of Grode et al. US 2020/0179502 June 11 2020 is withdrawn in view of the amendment to the claims.
The rejection of claim 32 on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 10,525,118 (‘118) and Grode et al. US 2020/0179502 June 11 2020 as applied to claim 22 above, further in view of Andrade et al. International Urology and Nephrology (2020) 52:1471-1476 is withdrawn in view of the amendment to the claims.
The rejection of claim 2-3, 22-25, 40 and 45 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 11,426,453 (‘453) is withdrawn in view of the cancellation of the claims.
The rejection of claim 32 on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 11,426,453 (‘453) as applied to claim 22 above, further in view of Andrade et al. International Urology and Nephrology (2020) 52:1471-1476 is withdrawn in view of the cancellation of claim 22.
The rejection of claim(s) 2-3, 22-25, 40 and 45 is/are under 35 U.S.C. 102(a)(1) as being anticipated by Grode et al. US 2020/0179502 June 11 2020 is withdrawn in view of the cancellation of the claims.
The rejection of claim(s) 22 and 37 under 35 U.S.C. 103 as being unpatentable over Grode et al. US 2020/0179502 June 11 2020 is withdrawn in view of the amendment to cancel claim 22.
The rejection of claim(s) 22 and 32 under 35 U.S.C. 103 as being unpatentable over Grode et al. US 2020/0179502 June 11 2020 in view of Andrade et al. International Urology and Nephrology (2020) 52:1471-1476 is withdrawn in view of the amendment to cancel claim 22.
Claim Rejections - 35 USC § 112 Maintained
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 1, 21, 26-39 and 41-44 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.
Claim 1 and 21 recite in-part:
(b) a phagolysosomal escape domain encoded by a nucleic acid molecule selected from
(i) a nucleotide sequence comprising nucleotides 211-1722 as shown in SEQ ID NO: 1,
(ii) a nucleotide sequence which encodes the same amino acid sequence as the sequence from (i), and
(iii) a nucleotide sequence hybridizing under stringent conditions with the sequence from (i) or (ii), wherein said stringent conditions comprise washing for one hour with 0.2 X or 1 X SSC and 0.1% SDS at a temperature of 55-68°C.
Applicant’s argument:
A person of ordinary skill in the art would understand with
reasonable certainty the scope of what amended claim 1 recites. It is routine in the art to identify nucleotide sequences that hybridize under specified stringent conditions and to determine whether such sequences encode the relevant amino acid sequence/domain. The claim, read in light of the specification, informs a person of ordinary skill in the art that the claimed phagolysosomal escape domain is encoded by the expressly recited sequence, by a sequence encoding the same amino acid sequence, or by a sequence hybridizing under the expressly recited stringent conditions with those sequences.
Response to Applicant’s Argument
Applicants argument has been considered but is not found persuasive. As explained in the prior rejection a nucleotide sequence hybridizing under stringent conditions with the sequence from (i) or (ii) includes the reverse complement sequence. The reverse complement of a DNA sequence is the non-coding strand or anti-sense strand -i.e. a DNA sequence is usually not read in both directions. See “Antisense” taken from Https:// www genome gov/genetics- glossary/antisense retrieved 3/20/21 (cite #9 IDS filed 4/4/25).
Applicants do not provide any evidence that the reverse complement (non-coding strand) which would hybridize with a nucleotide sequence comprising nucleotides 211-1722 as shown in SEQ ID NO: 1 encodes a phagolysosomal domain. There is no evidence that a nucleotide sequence comprising nucleotides 211-1722 as shown in SEQ ID NO: 1 hybridizes with itself and this is impossible because of base pairing rules.
Because the art teaches that a reverse complement of a coding sequence is non-coding, a nucleotide sequence hybridizing under stringent conditions with the sequence from (i) or (ii), wherein said stringent conditions comprise washing for one hour with 0.2 X or 1 X SSC and 0.1% SDS at a temperature of 55-68°C will not code for a phagolysosomal escape domain.
Applicants can obviate the rejection by stating provided that there is written description support:
“(iii) a nucleotide sequence hybridizing under stringent conditions with a full length complement of the sequence from (i) or (ii), wherein said stringent conditions comprise washing for one hour with 0.2 X or 1X SSC and 0.1% SDS at a temperature of 55 - 68° C.”
A nucleotide sequence hybridizing under stringent conditions with a full length complement of the sequence from (i) or (ii) would encode the phagolysosomal escape domain of (i).
Claim Rejections - 35 USC § 102 Maintained
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1, 21, 26-31 and 33-39 and 41-44 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Grode et al. US 2020/0179502 June 11 2020.
Claim 1: Grode disclose a recombinant Mycobacterium bovis cell which is urease deficient M. bovis BCG cell from Danish subtype Prague (paragraph 11, 18, ) which comprises a recombinant nucleic acid molecule without a functional selection maker gene which expresses an Ag85B/Hly fusion protein (paragraph 38);
Wherein the nucleic acid molecule encodes a fusion polypeptide comprising:
(a) a domain capable of eliciting an immune response comprising the sequence from aa.41 to aa.51 in SEQ ID No.2, and
(b) a Listeria phagolysosomal escape domain encoded by a nucleic acid molecule selected from (i) a nucleotide sequence comprising nucleotides 211-1722 as shown in SEQ ID No.1, (ii) a nucleotide sequence which encodes the same amino acid sequence as the sequence from (i), and
(iii) a nucleotide sequence hybridizing under stringent conditions with the sequence from (i) or (ii), wherein said stringent conditions comprising washing for 0.2×SSC and 0.1% SDS at 55° C, preferably at 62° C. and more preferably at 68° C. See paragraph 22.
The recombinant M. bovis cell is in combination with a carrier. See paragraph 31.
See also claims 1-15 of Grode et al.
With regards to claim 1, the recitation of “for administration as an immunotherapeutic agent to a subject suffering from recurrent non-muscle-invasive bladder carcinoma, as a second-line therapy, wherein the human subject has relapsed and/or in whom the bladder carcinoma has progressed after first-line immunotherapy with standard BCG, and wherein the bladder carcinoma recurrence is inhibited for a time period of at least 1 year” is an intended use of the claimed recombinant Mycobacterium cell. A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention to patentably distinguish the claimed invention from the recombinant Mycobacterium of the Grode et al. The recombinant Mycobacterium of the Grode et al meets the structural limitations of the instant claims and therefore it is capable of performing the intended use recited in claim 1.
Claim 21 – Grode disclose a method for the immunotherapeutic treatment of non-muscle invasive bladder carcinoma (paragraph 35) that is recurrent in a subject wherein the subject is suffering from said recurrent non-muscle invasive bladder carcinoma after first line standard BCG therapy is conducted (i.e. the carcinoma has relapsed or the bladder carcinoma has progressed after the first-line therapy with standard BCG (paragraph 15, 29 and example 3); the method comprising administering to said subject as a second line therapy:
a recombinant Mycobacterium bovis cell which is urease deficient M. bovis BCG cell from Danish subtype Prague (paragraph 11, 18, ) which comprises a recombinant nucleic acid molecule without a functional selection maker gene which expresses an Ag85B/Hly fusion protein (paragraph 38);
Wherein the nucleic acid molecule encodes a fusion polypeptide comprising:
(a) a domain capable of eliciting an immune response comprising the sequence from aa.41 to aa.51 in SEQ ID No.2, and
(b) a Listeria phagolysosomal escape domain encoded by a nucleic acid molecule selected from (i) a nucleotide sequence comprising nucleotides 211-1722 as shown in SEQ ID No.1, (ii) a nucleotide sequence which encodes the same amino acid sequence as the sequence from (i), and
(iii) a nucleotide sequence hybridizing under stringent conditions with the sequence from (i) or (ii), wherein said stringent conditions comprising washing for 0.2×SSC and 0.1% SDS at 55° C, preferably at 62° C. and more preferably at 68° C. See paragraph 22.
The recombinant M. bovis cell is in combination with a carrier. See paragraph 31.
See also claims 1-15 of Grode et al.
See paragraph 29, example 3, paragraphs 47-49 “phase i/ii open label clinical trial assessing safety and efficacy of intravesical instillation of recombinant BCG (rBCG) in human patients with recurrent non-muscle invasive bladder cancer after standard BCG therapy”.
Claim 26 - Grode (paragraph 28, 47-49, claim 1) disclose the administration comprises vesicular instillation into said human subject's urinary bladder.
Claim 27 - Grode (paragraph 29, 47-49) wherein the human subject has previously undergone at least one unsuccessful first-line therapy of bladder carcinoma.
Claim 28 - Grode (paragraph 29, 47-49) said human subject has previously undergone at least one unsuccessful (recurrent) first-line therapy (standard BCG) of bladder carcinoma comprising an immunotherapy (rBCG).
Claim 29 - Grode (paragraph 29. 47-49) said at least one unsuccessful first-line therapy of bladder carcinoma comprising an immunotherapy is an immunotherapy with standard BCG.
Claim 30 - Grode (29, paragraph 47-49) said human subject has previously undergone at least one unsuccessful (recurrent) first-line therapy of bladder carcinoma comprising another local treatment (standard BCG).
Claim 31 - Grode (paragraph 47-49) disclose said human subject has previously undergone at least one unsuccessful first-line therapy of bladder carcinoma with standard BCG.
Claim 33 - Grode (paragraph 35, 47-49, claims 10-11) disclose the immunotherapeutic agent is administered into the bladder according to a schedule involving weekly instillations.
Claim 34 - Grode (paragraph 32-35, 47-49, claims 10-11) disclose wherein the immunotherapeutic agent is administered into the bladder according to a schedule involving weekly instillations during (i) an induction phase and (ii) a maintenance phase of at least one year.
Claim 35 - Grode (paragraph 35, 47-49, claims 10-11) disclose the method of claim 34, wherein (i) the induction phase has 6 weekly instillations, (ii) the maintenance phase of at least one year has a first maintenance phase after about 3 months with 3 weekly instillations, a second maintenance phase after about 6 months with 3 weekly instillations and a third maintenance phase after about 12 months with 3 weekly instillations.
Claim 36 - Grode disclose the recombinant Mycobacterium cell is administered at a dose of from about 107 to 5 x 109 CFU i.e. overlapping with the disclosed about 106 to 1010 CFU in claim 12.
Claim 37 –Grode disclose a dose of from about 2 x 109 CFU per administration i.e. 109 CFU. See paragraph 30.
Claim 38 - Grode disclose disease recurrence is inhibited for at least 1 year as evidenced by maintenance phase after about 12 months. See claim 11. In addition, the method of claim 22 is disclosed and thus the same result should occur i.e. disease recurrence is inhibited for a time period selected from the group consisting of at least 1 year, at least 2 years, at least 3 years and at least 4 years.
Claim 39- the method of claim 21 is disclosed and thus the immunotherapy provides a disease- free time period selected from the group consisting of at least 1 year, at least 2 years, at least 3 years and at least 4 years.
Claim 41- the method of claim 21 is disclosed and thus bladder carcinoma recurrence is blocked for at least one further year in a subject without disease recurrence for a time period of 2 years after treatment starts.
Claim 42 - the method of claim 21 is disclosed and thus overall survival is increased compared to a human subject without treatment in a time period of at least 1 year.
Claim 43 - the method of claim 21 is disclosed and thus overall survival is increased compared to a human subject without treatment in a time period of at least 2 years, of at least 3 years or of at least 4 years.
Claim 44 - the method of claim 21 is disclosed and thus the need of cystectomy is reduced or avoided for a time period selected from the group consisting of at least a 1 year, at least 2 years, at least 3 years and at least 4 years.
Applicant’s Argument:
Applicants argue that Grode does not disclose one or more features recited in amended claim 1. For example, Grode '502 does not disclose "a recombinant Mycobacterium cell in combination with a carrier suitable for administration as an immunotherapeutic agent to a subject suffering from recurrent non-muscle-invasive bladder
carcinoma, as a second-line therapy, and wherein the human subject has relapsed and/or in whom the bladder carcinoma has progressed after first-line immunotherapy with standard BCG and wherein the bladder carcinoma recurrence is inhibited for a time period of at least 1 year," as recited in amended claim 1.
Response to Applicant’s Argument:
In response to applicant's argument, a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. The recombinant Mycobacterium of the Grode et al meets the structural limitations of the instant claims and therefore it is capable of performing the intended use recited in claim 1.
Applicant’s Argument
As amended, claim 1 now requires, inter alia, (i) recurrent non-muscle-invasive bladder carcinoma, (ii) administration as a second-line therapy, (iii) a human subject who has relapsed and/or in whom the bladder carcinoma has progressed after first-line immunotherapy with standard BCG, and (iv) inhibition of bladder carcinoma recurrence for a time period of at least 1 year. Grode '502 does not disclose, expressly or inherently, that combination of limitations.
Response to Applicant’s Argument
Applicants argument has been considered but is not found persuasive. Grode et al anticipates the recombinant Mycobacterium cell. Applicants argument are directed to an intended use limitations. A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. The recombinant Mycobacterium of the Grode et al meets the structural limitations of the instant claims and therefore it is capable of performing the intended use recited in claim 1.
Applicants Argument:
Claim 21 is patentable over the cited reference because Grode '502 does not disclose one or more features recited in amended claim 21. For example, Grode '502 does not disclose a "method for the immunotherapeutic treatment of non-muscle-invasive bladder carcinoma in a subject suffering from recurrent non-muscle-invasive bladder cancer which has relapsed and/or in whom the bladder carcinoma has progressed after a first-line immunotherapy with standard BCG, comprising administering to said subject as a second-line therapy a recombinant Mycobacterium cell," as recited in amended claim 21.
Response to Applicant’s Argument
Grode et al disclose all the features of claim 21 as set forth in the rejection above.
Claim 21 – Grode disclose a method for the immunotherapeutic treatment of non-muscle invasive bladder carcinoma (paragraph 35) that is recurrent in a subject wherein the subject is suffering said recurrent non-muscle invasive bladder carcinoma after standard BCG therapy is conducted (i.e. the carcinoma has relapsed or the bladder carcinoma has progressed after the first-line therapy with standard BCG (paragraph 15, 29 and example 3); the method comprising to said subject as a second line therapy:
a recombinant Mycobacterium bovis cell which is urease deficient M. bovis BCG cell from Danish subtype Prague (paragraph 11, 18, ) which comprises a recombinant nucleic acid molecule without a functional selection maker gene which expresses an Ag85B/Hly fusion protein (paragraph 38);
Wherein the nucleic acid molecule encodes a fusion polypeptide comprising:
(a) a domain capable of eliciting an immune response comprising the sequence from aa.41 to aa.51 in SEQ ID No.2, and
(b) a Listeria phagolysosomal escape domain encoded by a nucleic acid molecule selected from (i) a nucleotide sequence comprising nucleotides 211-1722 as shown in SEQ ID No.1, (ii) a nucleotide sequence which encodes the same amino acid sequence as the sequence from (i), and
(iii) a nucleotide sequence hybridizing under stringent conditions with the sequence from (i) or (ii), wherein said stringent conditions comprising washing for 0.2×SSC and 0.1% SDS at 55° C, preferably at 62° C. and more preferably at 68° C. See paragraph 22.
The recombinant M. bovis cell is in combination with a carrier. See paragraph 31.
See also claims 1-15 of Grode et al.
See paragraph 29, example 3, paragraphs 47-49 “phase i/ii open label clinical trial assessing safety and efficacy of intravesical instillation of recombinant BCG (rBCG) in human patients with recurrent non-muscle invasive bladder cancer after standard BCG therapy”.
Claim Rejections - 35 USC § 103 Maintained
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 21 and 37 is/are rejected under 35 U.S.C. 103 as being unpatentable over Grode et al. US 2020/0179502 June 11 2020.
Claim 21 – Grode disclose a method for the immunotherapeutic treatment of non-muscle invasive bladder carcinoma (paragraph 35) that is recurrent in a subject wherein the subject is suffering said recurrent non-muscle invasive bladder carcinoma after standard BCG therapy is conducted (i.e. the carcinoma has relapsed or the bladder carcinoma has progressed after the first-line therapy with standard BCG (paragraph 15, 29 and example 3); the method comprising to said subject as a second line therapy:
a recombinant Mycobacterium bovis cell which is urease deficient M. bovis BCG cell from Danish subtype Prague (paragraph 11, 18, ) which comprises a recombinant nucleic acid molecule without a functional selection maker gene which expresses an Ag85B/Hly fusion protein (paragraph 38);
Wherein the nucleic acid molecule encodes a fusion polypeptide comprising:
(a) a domain capable of eliciting an immune response comprising the sequence from aa.41 to aa.51 in SEQ ID No.2, and
(b) a Listeria phagolysosomal escape domain encoded by a nucleic acid molecule selected from (i) a nucleotide sequence comprising nucleotides 211-1722 as shown in SEQ ID No.1, (ii) a nucleotide sequence which encodes the same amino acid sequence as the sequence from (i), and
(iii) a nucleotide sequence hybridizing under stringent conditions with the sequence from (i) or (ii), wherein said stringent conditions comprising washing for 0.2×SSC and 0.1% SDS at 55° C, preferably at 62° C. and more preferably at 68° C. See paragraph 22.
The recombinant M. bovis cell is in combination with a carrier. See paragraph 31.
See also claims 1-15 of Grode et al.
See paragraph 29, example 3, paragraphs 47-49 “phase i/ii open label clinical trial assessing safety and efficacy of intravesical instillation of recombinant BCG (rBCG) in human patients with recurrent non-muscle invasive bladder cancer after standard BCG therapy”.
Grode disclose the recombinant Mycobacterium cell is administered at a dose of from about 107 to 5 x 109 CFU i.e. overlapping with the disclosed about 106 to 1010 CFU in claim 12. See paragraph 30.
Grode does not disclose a dose of from 2 x 109 CFU per administration.
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Grode et al disclose the recombinant Mycobacterium cell is administered at a dose of 107 to 5 x 109 CFU per administration and administering 2 X109 CFU per administration would not have been inventive because this dose could have been discovered by one of ordinary skill in the art as of the effective filing date by routine experimentation. Moreover, 2 X109 CFU per administration falls within the range disclosed by Grode et al which is 107 to 5 x 109 CFU per administration and thus the instant range is obvious over the disclosed range of Grode et al.
Applicant’s Argument:
Grode '502 does not disclose and would not have suggested treatment of recurrent non-muscle-invasive bladder carcinoma as a second-line therapy in a human subject who has relapsed and/or in whom the bladder carcinoma has progressed after first-line immunotherapy with standard BCG, together with the therapeutic limitation that bladder carcinoma recurrence is inhibited for a time period of at least 1 year, as recited in amended claim 21 and reflected in amended claim 1. Furthermore, as conceded by the Patent Office, Grode '502 "does not disclose a dose of from 2 X 10⁹ CFU per administration" of the claimed recombinant BCG in the method of amended claim 21, from which claim 37 depends. Applicant submits that routine experimentation would not have rendered the presently claimed subject matter obvious.
The claims are directed to the immunotherapy of recurrent non-muscle-invasive bladder carcinoma in a specifically defined patient population, namely, human subjects who have relapsed and/or in whom the bladder carcinoma has progressed after first-line immunotherapy with standard BCG. The Patent Office has failed to establish that a person of ordinary skill in the art would have had a reasonable expectation that selecting the presently claimed dose would achieve the claimed and described long-term therapeutic benefit in that specifically recited second-line treatment setting. In particular, the cited reference does not provide a basis to expect the long-term therapeutic effect reflected in the present claims, including bladder carcinoma recurrence being inhibited for a time period of at least 1 year. The mere report that VPM1002BC was in a phase I/II trial does not establish any actual therapeutic or pharmacological effect, much less render obvious the presently claimed dose in the context of the amended claims.
Response to Applicant’s Argument:
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., Grode '502 does not disclose and would not have suggested treatment of recurrent non-muscle-invasive bladder carcinoma as a second-line therapy in a human subject who has relapsed and/or in whom the bladder carcinoma has progressed after first-line immunotherapy with standard BCG, together with the therapeutic limitation that bladder carcinoma recurrence is inhibited for a time period of at least 1 year, as recited in amended claim 21 are not recited in the rejected claim 21 and 37. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Applicants argument that the Patent Office has failed to establish that a person of ordinary skill in the art would have had a reasonable expectation that selecting the presently claimed dose would achieve the claimed and described long-term therapeutic benefit in that specifically recited second-line treatment setting and that particular, the cited reference does not provide a basis to expect the long-term therapeutic effect reflected in the present claims, including bladder carcinoma recurrence being inhibited for a time period of at least 1 year.
The instant claim 21 and claim 37 does not recite any long term therapeutic effect including bladder carcinoma recurrence being inhibited for a time period of at least 1 year.
Grode et al disclose the recombinant Mycobacterium cell is administered at a dose of 107 to 5 x 109 CFU per administration and administering 2 X109 CFU per administration would not have been prima facie obvious because this dose could have been discovered by one of ordinary skill in the art as of the effective filing date by routine experimentation. Moreover, 2 X109 CFU per administration is within the disclosed range of 107 to 5 x 109 CFU per administration, therefore administering 2 X109 CFU per administration would have been prima facie obvious to a person of ordinary skill in the art as of the effective filing date in view of the disclosure of 107 to 5 x 109 CFU per administration.
Claim(s) 21 and 32 is/are rejected under 35 U.S.C. 103 as being unpatentable over Grode et al. US 2020/0179502 June 11 2020 in view of Andrade et al. International Urology and Nephrology (2020) 52:1471-1476.
Claim 21 – Grode disclose a method for the immunotherapeutic treatment of non-muscle invasive bladder carcinoma (paragraph 35) that is recurrent in a subject wherein the subject is suffering said recurrent non-muscle invasive bladder carcinoma after standard BCG therapy is conducted (i.e. the carcinoma has relapsed or the bladder carcinoma has progressed after the first-line therapy with standard BCG (paragraph 15, 29 and example 3); the method comprising to said subject as a second line therapy:
a recombinant Mycobacterium bovis cell which is urease deficient M. bovis BCG cell from Danish subtype Prague (paragraph 11, 18, ) which comprises a recombinant nucleic acid molecule without a functional selection maker gene which expresses an Ag85B/Hly fusion protein (paragraph 38);
Wherein the nucleic acid molecule encodes a fusion polypeptide comprising:
(a) a domain capable of eliciting an immune response comprising the sequence from aa.41 to aa.51 in SEQ ID No.2, and
(b) a Listeria phagolysosomal escape domain encoded by a nucleic acid molecule selected from (i) a nucleotide sequence comprising nucleotides 211-1722 as shown in SEQ ID No.1, (ii) a nucleotide sequence which encodes the same amino acid sequence as the sequence from (i), and
(iii) a nucleotide sequence hybridizing under stringent conditions with the sequence from (i) or (ii), wherein said stringent conditions comprising washing for 0.2×SSC and 0.1% SDS at 55° C, preferably at 62° C. and more preferably at 68° C. See paragraph 22.
The recombinant M. bovis cell is in combination with a carrier. See paragraph 31.
See also claims 1-15 of Grode et al.
See paragraph 29, example 3, paragraphs 47-49 “phase i/ii open label clinical trial assessing safety and efficacy of intravesical instillation of recombinant BCG (rBCG) in human patients with recurrent non-muscle invasive bladder cancer after standard BCG therapy”.
Grode does not disclose the subject is a smoker.
Andrade et al disclose that relapse (recurrent bladder cancer) after standard BCG treatment is a predictive for smokers. See title, abstract and under discussion p. 1474 column 1.
It would have been prima facie obvious to a person of ordinary skill in the art as of the effective filing date of the instant invention to have practiced the method of Grode et al in smoker patients who have had a relapsed bladder cancer after standard BCG treatment, thus resulting in the instant invention with a reasonable expectation of success. The motivation to do so is that Andrade et al disclose that smokers being treated with standard BCG for bladder cancer are most likely to have a relapse (recurrence) of the bladder carcinoma.
Applicant’s Argument
Claim 32 is patentable over the cited references because the cited combination does not disclose or suggest one or more features recited in amended claim 21, from which claim 32 depends. For example, the cited references do not disclose and would not have suggested treatment of recurrent non-muscle-invasive bladder carcinoma as a second-line therapy in a human subject who has relapsed and/or in whom the bladder carcinoma has progressed after first-line immunotherapy with standard BCG, together with the therapeutic limitation that bladder carcinoma recurrence is inhibited for a time period of at least 1 year, as recited in amended claim 21 and reflected in amended claim 1. Applicant further submits that even if Andrade is considered for the limited proposition identified by the Patent Office as outlined above, Andrade does not cure the deficiencies of Grode '502. Claim 32 depends from amended claim 21 and further recites that the subject is a smoker. However, the cited combination of references still does not disclose or suggest the newly amended claim limitations of independent claim 21 requiring treatment of recurrent NMIBC as a second-line therapy in a human subject who has relapsed and/or in whom the bladder carcinoma has progressed after first-line immunotherapy with standard BCG, together with the recited therapeutic limitation that bladder carcinoma recurrence is inhibited for a time period of at least 1 year.
Response to Applicant’s Argument
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., Grode '502 does not disclose and would not have suggested treatment of recurrent non-muscle-invasive bladder carcinoma as a second-line therapy in a human subject who has relapsed and/or in whom the bladder carcinoma has progressed after first-line immunotherapy with standard BCG, together with the therapeutic limitation that bladder carcinoma recurrence is inhibited for a time period of at least 1 year, as recited in amended claim 21) are not recited in the rejected claim 21 and 32. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).]
For this reason, the combination of Grode et al and Andrade et al renders the instant claims prima facie obvious.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to
Claim 1 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 9084749 (‘749). Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘749 claims disclose:
A vaccine comprising a recombinant Mycobacterium bovis cell Danish subtype Prague: “wherein the recombinant Mycobacterium is a recombinant Mycobacterium bovis (BCG) cell from strain Danish subtype Prague”
which comprises a recombinant nucleic acid molecule encoding a fusion polypeptide “a recombinant Mycobacterium which is urease-deficient and which comprises a recombinant nucleic acid molecule encoding a fusion polypeptide” comprising:
a domain capable of eliciting an immune response encoded by nucleotides 121-153 of SEQ ID NO: 1 which corresponds to aa 41 to 51 of SEQ ID NO: 2,
and
a Listeria phagolysosomal escape domain encoded by a nucleic acid comprising nucleotides 211-1722 of SEQ ID NO: 1.
The ‘749 claims does not disclose the recombinant nucleic acid does not comprise any functional selection marker and moreover ‘749 claims disclose the recombinant Mycobacterium cell does not carry an antibiotic resistance gene which corresponds to a functional selection marker.
Since the ‘749 claims disclose a vaccine, the recombinant Mycobacterium does not exist in a vacuum in the composition and the vaccine composition necessarily comprises a carrier suitable for administration since it is a vaccine.
The recitation of “for administration as an immunotherapeutic agent to a subject suffering from recurrent non-muscle-invasive bladder carcinoma, as a second-line therapy, wherein the human subject has relapsed and/or in whom the bladder carcinoma has progressed after first-line immunotherapy with standard BCG, and wherein the bladder carcinoma recurrence is inhibited for a time period of at least 1 year” is an intended use of the claimed recombinant Mycobacterium cell. A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and those of the ‘749 claims to patentably distinguish the claimed invention from the recombinant Mycobacterium of the ‘749 claims. The recombinant Mycobacterium of the ‘749 claim meets the structural limitations of the instant claims and therefore it is capable of performing the intended use.
Applicants argument:
Applicants argue that claim 1 of Grode is directed to a vaccine for use in humans comprising a recombinant Mycobacterium cell and claim 9 of Grode limits the vaccine to use against tuberculosis and claim 11 limits the vaccine of claim 2 to a Mycobacterium naïve subject who is a newborn and claim 6 requires intradermal administration, claim 7 requires a single dose or two or more doses and claim 5 discloses the amounts in CFU.
Applicants state in contrast claim 1 of the present application B is directed to a recombinant Mycobacterium cell in combination with a carrier suitable for administration as an immunotherapeutic agent to a subject suffering from recurrent non-muscle-invasive bladder carcinoma, as a second-line therapy, wherein the human subject has relapsed and/or in whom the bladder carcinoma has progressed after first-line immunotherapy with standard BCG, and wherein the bladder carcinoma recurrence is inhibited for a time period of at least 1 year and thus, the pending claims are directed neither to a tuberculosis vaccine nor to vaccination of a Mycobacterium-naive subject, much less a newborn. Applicants state that the pending claims recite the intradermal administration, low claimed dose range, or limited dose schedule recited in Grode '749.
Response to Applicant’s Argument
Applicants argument has been carefully considered but is not found persuasive. This is because claim 1 of the instant application is drawn to a product i.e. the recombinant Mycobacterium cell in combination with a carrier suitable for administration. The recitation of “for administration as an immunotherapeutic agent to a subject suffering from recurrent non-muscle-invasive bladder carcinoma, as a second-line therapy, wherein the human subject has relapsed and/or in whom the bladder carcinoma has progressed after first-line immunotherapy with standard BCG, and wherein the bladder carcinoma recurrence is inhibited for a time period of at least 1 year” is an intended use of the claimed recombinant Mycobacterium cell. A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and those of the ‘749 claims to patentably distinguish the claimed invention from the recombinant Mycobacterium of the ‘749 claims. The recombinant Mycobacterium of the ‘749 claim meets the structural limitations of the instant claims and therefore it is capable of performing the intended use.
Claim 1 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 11,426,453 (‘453). Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘453 claims disclose:
Claim 1: A recombinant Mycobacterium bovis BCG cell which comprises a recombinant nucleic acid molecule encoding a fusion polypeptide comprising: (a) a domain capable of eliciting an immune response, and (b) a Listeria phagolysosomal escape domain in combination with a carrier where in the recombinant nucleic acid molecule does not comprise any functional selection marker.
The ‘453 claims disclose that M. bovis BCG cell from strain Danish subtype Prague.
The ’453 claims disclose cell is a urease-deficient cell.
The ‘453 claims disclose that the domain capable of eliciting an immune response is an immunogenic peptide or polypeptide from M. bovis or M. tuberculosis.
The ‘453 claims disclose that the domain capable of eliciting an immune response comprising the amino acid sequence from aa.41 to aa.51 of SEQ ID NO: 2 and that the Listeria phagolysosomal escape domain encoded by a nucleic acid molecule selected from
a nucleotide sequence comprising nucleotides 211-1722 as shown in SEQ ID No.1,
a nucleotide sequence which encodes the same amino acid sequence as the sequence from (i), and
a nucleotide sequence hybridizing under stringent conditions with the f sequence from (i) or (ii ) wherein said stringent conditions comprise washing for one hour with 0.2× or 1× SSC and 0.1% SDS at a temperature of 55-68° C. See claim 4 of the ‘453 claims
The ‘453 claims disclose the recombinant Mycobacterium cell is in combination with a liquid carrier.
The ‘453 claim 3 discloses that the recombinant nucleic acid molecule does not comprise any functional selection marker.
The teachings of the “453 claims renders prima facie obvious the recombinant Mycobacterium of instant claim 1.
With regards to claim 1, the recitation of “for administration as an immunotherapeutic agent to a subject suffering from recurrent non-muscle-invasive bladder carcinoma, as a second-line therapy, wherein the human subject has relapsed and/or in whom the bladder carcinoma has progressed after first-line immunotherapy with standard BCG, and wherein the bladder carcinoma recurrence is inhibited for a time period of at least 1 year” is an intended use of the claimed recombinant Mycobacterium cell. A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and those of the ‘453 claims to patentably distinguish the claimed invention from the recombinant Mycobacterium and the carrier of the ‘453 claims. The recombinant Mycobacterium and the carrier of the ‘453 claims meets the structural limitations of the instant claims and therefore it is capable of performing the intended use.
Applicant’s Argument
Claim 1 is patentable over claims 1-17 of Grode '453 because claims 1-17 of Grode '453 do not recite one or more features recited in amended claim 1. For example, claims 1-17 of Grode '453 do not recite a recombinant Mycobacterium cell in "combination with a carrier suitable for administration as an immunotherapeutic agent to a subject suffering from recurrent non-muscle-invasive bladder carcinoma, as a second-line therapy, and wherein the human subject has relapsed and/or in whom the bladder carcinoma has progressed after first-line immunotherapy with standard BCG and wherein the bladder carcinoma recurrence is inhibited for a time period of at least 1 year," as recited in amended claim 1.
Claim 1 of the present application is patentably distinct. As amended, claim 1 requires treatment of recurrent NMIBC as second-line therapy in a human subject who has relapsed and/or in whom the bladder carcinoma has progressed after first-line immunotherapy with standard BCG, and further requires that bladder carcinoma recurrence is inhibited for at least one year. Those limitations are not recited in claims 1-17 of Grode '453. Even Grode '453 claim 17, which recites lyophilized formulation, reconstitution, vesicular instillation, and a weekly induction/maintenance schedule, does not recite the specifically amended patient subgroup, does not recite that the therapy is second-line after relapse and/or progression following first-line standard BCG, and does not recite the claimed one-year inhibition of recurrence.
Response to Applicant’s Argument:
Applicant’s argument has been considered but is not found persuasive. The limitations being relied upon not disclosed by the ‘453 claims are drawn to the intended use of the recombinant Mycobacterium cell in combination with a carrier. Claim 1 is not a method claim.
With regards to claim 1, the recitation of “for administration as an immunotherapeutic agent to a subject suffering from recurrent non-muscle-invasive bladder carcinoma, as a second-line therapy, wherein the human subject has relapsed and/or in whom the bladder carcinoma has progressed after first-line immunotherapy with standard BCG, and wherein the bladder carcinoma recurrence is inhibited for a time period of at least 1 year” is an intended use of the claimed recombinant Mycobacterium cell. A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and those of the ‘453 claims to patentably distinguish the claimed invention from the recombinant Mycobacterium and the carrier of the ‘453 claims. The recombinant Mycobacterium and the carrier of the ‘453 claims meets the structural limitations of the instant claims and therefore it is capable of performing the intended use.
Claims 21, 26-31,33-39 and 41-44 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 and 9-17 of U.S. Patent No. 11,426,453 (‘453). Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘453 claims disclose:
Claim 21 – The ‘453 claims disclose a method for the immunotherapeutic treatment of bladder carcinoma and discloses that the bladder carcinoma is a non-muscle-invasive bladder carcinoma (see claim 6) in a human subject in need thereof suffering, comprising administering to said subject as a second-line therapy and the “453 claim disclose the bladder carcinoma can be a recurrent bladder carcinoma in a patient who has been previously treated with standard BCG (see claim 9) which corresponds to “subject suffering from recurrent non-muscle bladder cancer which has relapsed and/or in whom the bladder carcinoma has progressed after a first-line immunotherapy with standard BCG”, wherein the recombinant Mycobacterium cell:
Is a recombinant Mycobacterium bovis BCG cell which comprises a recombinant nucleic acid molecule encoding a fusion polypeptide comprising: (a) a domain capable of eliciting an immune response, and (b) a Listeria phagolysosomal escape domain in combination with a carrier where in the recombinant nucleic acid molecule does not comprise any functional selection marker.
The ‘453 claims disclose that M. bovis BCG cell is the strain Danish subtype Prague.
The ’453 claims disclose cell is a urease-deficient cell.
The ‘453 claims disclose that the domain capable of eliciting an immune response is an immunogenic peptide or polypeptide from M. bovis or M. tuberculosis.
The ‘453 claims disclose that the domain capable of eliciting an immune response comprising the amino acid sequence from aa.41 to aa.51 of SEQ ID NO: 2 and that the a Listeria phagolysosomal escape domain encoded by a nucleic acid molecule selected from
a nucleotide sequence comprising nucleotides 211-1722 as shown in SEQ ID No.1,
a nucleotide sequence which encodes the same amino acid sequence as the sequence from (i), and
a nucleotide sequence hybridizing under stringent conditions with the sequence from (i) or (ii ) wherein said stringent conditions comprise washing for one hour with 0.2× or 1× SSC and 0.1% SDS at a temperature of 55-68° C. See claim 4 of the ‘453 claims
The ‘453 claims disclose the recombinant Mycobacterium cell is in combination with a liquid carrier.
The ‘453 claim 3 discloses that the recombinant nucleic acid molecule does not comprise any functional selection marker.
Thus, the teachings of the ‘453 claims renders instant claim 21 prima facie obvious.
Claim 26 - the ‘453 claims disclose the administration comprises vesicular instillation into said human subject's urinary bladder. See claim 11.
27 - The ‘453 claims disclose human subject has previously undergone at least one unsuccessful first-line therapy of bladder carcinoma i.e. the instillation during an induction phase followed by maintenance doses (see claim 10).
28 - The ‘453 claims disclose human subject has previously undergone at least one unsuccessful (recurrent) first-line therapy (standard BCG) of bladder carcinoma comprising an immunotherapy. See claim 9.
29 - The ‘453 claims disclose at least one unsuccessful first-line therapy of bladder carcinoma comprising an immunotherapy is an immunotherapy with standard BCG. See claim 9.
30 - The ‘453 claims disclose wherein said human subject has previously undergone at least one unsuccessful (recurrent) first-line therapy of bladder carcinoma comprising another local treatment (standard BCG).
31 - The ‘453 claims disclose wherein said human subject has previously undergone at least one unsuccessful first-line therapy of bladder carcinoma with standard BCG.
33 - The ‘453 claims disclose wherein the immunotherapeutic agent is administered into the bladder according to a schedule involving weekly instillations. See claim 10.
34 - The ‘453 claims disclose wherein the immunotherapeutic agent is administered into the bladder according to a schedule involving weekly instillations during (i) an induction phase and (ii) a maintenance phase of at least one year. See claim 10-11.
35 - The ‘453 claims disclose wherein (i) the induction phase has 6 weekly instillations, (ii) the maintenance phase of at least one year has a first maintenance phase after 3 months with 3 weekly instillations, a second maintenance phase after 6 months with 3 weekly instillations and a third maintenance phase after 12 months with 3 weekly instillations. See claim 11.
Claim 36 - The ‘453 claims disclose wherein the recombinant Mycobacterium cell is administered at a dose of from about 107 to 5 x 109 CFU i.e. overlapping with the disclosed amount of 106 to 1010 CFU in claim 12.
Claim 37 – the ‘453 discloses the about 106 to 1010 CFU per administration in claim 12 which renders prima facie obvious a dose of from 2 x 109 CFU per administration. Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). The ‘453 claims disclose the recombinant Mycobacterium cell is administered at a dose of from about 106 to 1010 CFU per administration and administering 2 X109 CFU per administration would not have been inventive because this dose could have been discovered by one of ordinary skill in the art as of the effective filing date by routine experimentation especially since the X109 CFU per administration falls within the disclosed range 2 X109 CFU per administration.
Claim 38 - The ‘453 claims disclose, wherein disease recurrence is inhibited for at least 1 year as evidenced by maintenance phase after about 12 months. See claim 11. In addition, the method of claim 21 is disclosed and thus the same result should occur i.e. disease recurrence is inhibited for a time period selected from the group consisting of at least 1 year, at least 2 years, at least 3 years and at least 4 years.
Claim 39- the method of claim 21 is disclosed and thus the immunotherapy provides a disease- free time period selected from the group consisting of at least 1 year, at least 2 years, at least 3 years and at least 4 years, for at least 30% of the patients.
Claim 41- the method of claim 21 is disclosed and thus disease recurrence is blocked for at least one further year in a subject without disease recurrence for a time period of 2 years after treatment starts.
Claim 42 - the method of claim 21 is disclosed and thus overall survival is increased compared to a human subject without treatment in a time period of at least 1 year.
Claim 43 - the method of claim 21 is disclosed and thus overall survival is increased compared to a human subject without treatment in a time period of at least 2 years, of at least 3 years or of at least 4 years.
Claim 44 - the method of claim 21 is disclosed and thus the need of cystectomy is reduced or avoided for a time period selected from the group consisting of at least a 1 year, at least 2 years, at least 3 years and at least 4 years.
Applicant’s argument
Claim 21 is patentable over claims 1-17 of Grode '453 because claims 1-17 of
Grode '453 do not recite one or more features recited in amended claim 21. For example, claims 1-17 of Grode '453 do not recite a method for treating "a subject suffering from recurrent non- muscle invasive bladder cancer which has relapsed and/or in whom the bladder carcinoma has progressed after a first-line immunotherapy with standard BCG in need thereof," wherein administration to said subject of the recombinant Mycobacterium cell is as "a second line therapy," as recited in amended claim 21.
Response to Applicant’s Argument
Applicant’s argument has been carefully considered but is not found persuasive.
The ‘453 claims disclose a method for the immunotherapeutic treatment of bladder carcinoma and discloses that the bladder carcinoma is a non-muscle-invasive bladder carcinoma (see claim 6) in a human subject in need thereof suffering, comprising administering to said subject as a second-line therapy a recombinant Mycobacterium cell and the “453 claim disclose the bladder carcinoma can be a recurrent bladder carcinoma in a patient who has been previously treated with standard BCG (see claim 9) which corresponds to “subject suffering from recurrent non-muscle bladder cancer which has relapsed and/or in whom the bladder carcinoma has progressed after a first-line immunotherapy with standard BCG”, wherein the recombinant Mycobacterium cell:
Is a recombinant Mycobacterium bovis BCG cell which comprises a recombinant nucleic acid molecule encoding a fusion polypeptide comprising: (a) a domain capable of eliciting an immune response, and (b) a Listeria phagolysosomal escape domain in combination with a carrier where in the recombinant nucleic acid molecule does not comprise any functional selection marker.
The ‘453 claims disclose that M. bovis BCG cell is from strain Danish subtype Prague.
The ’453 claims disclose cell is a urease-deficient cell.
The ‘453 claims disclose that the domain capable of eliciting an immune response is an immunogenic peptide or polypeptide from M. bovis or M. tuberculosis.
The ‘453 claims disclose that the domain capable of eliciting an immune response comprising the amino acid sequence from aa.41 to aa.51 of SEQ ID NO: 2 and that the a Listeria phagolysosomal escape domain encoded by a nucleic acid molecule selected from
a nucleotide sequence comprising nucleotides 211-1722 as shown in SEQ ID No.1,
a nucleotide sequence which encodes the same amino acid sequence as the sequence from (i), and
a nucleotide sequence hybridizing under stringent conditions with the full complement of the sequence from (i) or (ii ) wherein said stringent conditions comprise washing for one hour with 0.2× or 1× SSC and 0.1% SDS at a temperature of 55-68° C. See claim 4 of the ‘453 claims
Thus, the method of the ‘453 claims renders prima facie obvious claim 21.
Claim 32 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 11,426,453 (‘453) as applied to claim 21 above, further in view of Andrade et al. International Urology and Nephrology (2020) 52:1471-1476.
Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘453 claim 21 is set forth above, but does not disclose the subject is a smoker.
Andrade et al disclose that relapse (recurrent bladder cancer) after standard BCG treatment is a predictive for smokers. See title, abstract and under discussion p. 1474 column 1.
It would have been prima facie obvious to a person of ordinary skill in the art as of the effective filing date of the instant invention to have practiced the method of the 453 claims in smoker patients who have had a relapsed non-muscle invasive bladder cancer after standard BCG treatment, thus resulting in the instant invention with a reasonable expectation of success. The motivation to do so is that Andrade et al disclose that smokers being treated with standard BCG for bladder cancer are most likely to have a relapse (recurrence) of the bladder carcinoma.
Claim 1 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 10,525,118 (‘118) in view of Grode et al. US 2020/0179502 June 11 2020.
The ‘118 claims disclose a recombinant Mycobacterium cell, which is a urease C deficient, recombinant M. bovis BCG cell from strain Danish subtype Prague, which comprises a recombinant nucleic acid molecule encoding a fusion protein comprising:
a domain capable of eliciting an immune response; and
a Listeria phagolysosomal escape domain listeriolysin (Hly).
The ‘118 claims do not disclose that the recombinant nucleic acid molecule is without a functional selection marker.
The ‘118 claims do not disclose that
the domain capable of eliciting an immune response comprises the amino acid sequence from aa. 41 to aa. 51 in SEQ ID NO: 2; and
does not disclose the Listeria phagolysosomal escape domain encoded by a nucleic acid molecule selected from:
(i) a nucleotide sequence comprising nucleotides 211-1722 as shown in SEQ ID
NO: 1,
(ii) a nucleotide sequence which encodes the same amino acid sequence as the sequence from (i), and
(iii) a nucleotide sequence hybridizing under stringent conditions with the sequence from (i) or (ii), wherein said stringent conditions comprise washing for one hour with 0.2 X or 1X SSC and 0.1% SDS at a temperature of 55-68°C.
The recombinant Mycobacterium cell of the ‘118 claim would necessarily not exist in a vacuum and would be in combination with a carrier suitable for administration to the subject who it is administered to a evidenced by the administration disclosed by the ‘118 claims.
Grode disclose a method for the immunotherapeutic treatment of non-muscle invasive bladder carcinoma (paragraph 35) that is recurrent in a subject wherein the subject is suffering said recurrent non-muscle invasive bladder carcinoma after standard BCG therapy is conducted (i.e. the carcinoma has relapsed or the bladder carcinoma has progressed after the first-line therapy with standard BCG (paragraph 15, 29 and example 3); the method comprising to said subject as a second line therapy:
a recombinant Mycobacterium bovis cell which is urease deficient M. bovis BCG cell from Danish subtype Prague (paragraph 11, 18, ) which comprises a recombinant nucleic acid molecule without a functional selection maker gene which expresses an Ag85B/Hly fusion protein (paragraph 38);
Wherein the nucleic acid molecule encodes a fusion polypeptide comprising:
(a) a domain capable of eliciting an immune response comprising the sequence from aa.41 to aa.51 in SEQ ID No.2, and
(b) a Listeria phagolysosomal escape domain encoded by a nucleic acid molecule selected from (i) a nucleotide sequence comprising nucleotides 211-1722 as shown in SEQ ID No.1, (ii) a nucleotide sequence which encodes the same amino acid sequence as the sequence from (i), and
(iii) a nucleotide sequence hybridizing under stringent conditions with the sequence from (i) or (ii), wherein said stringent conditions comprising washing for 0.2×SSC and 0.1% SDS at 55° C, preferably at 62° C. and more preferably at 68° C. See paragraph 22.
It would have been prima facie obvious to a person of ordinary skill in the art as of the effective filing date to have a domain capable of eliciting an immune response comprising the sequence from aa.41 to aa.51 in SEQ ID No.2 as the domain capable of eliciting an immune response and the Listeria phagolysosomal escape domain encoded by a nucleic acid molecule selected from: (i) a nucleotide sequence comprising nucleotides 211-1722 as shown in SEQ ID NO: 1, (ii) a nucleotide sequence which encodes the same amino acid sequence as the sequence from (i), and (iii) a nucleotide sequence hybridizing under stringent conditions with the sequence from (i) or (ii), wherein said stringent conditions comprise washing for one hour with 0.2 X or 1X SSC and 0.1% SDS at a temperature of 55-68°C, as taught by Grode et al, thus resulting in the instant invention with a reasonable expectation of success.
The motivation to do so is that Grode et al disclose that a recombinant urease deficient recombinant M. bovis BCG cell from strain Danish which comprises a recombinant nucleic acid molecule without a functional selection marker (paragraph 38) encoding a fusion polypeptide comprising an Ag85B/Hly fusion protein can be used in the immunotherapy of non-muscle invasive bladder carcinoma, wherein the Ag85B is a domain capable of eliciting an immune response comprising the amino acid sequence from aa. 41 to aa. 51 in SEQ ID NO: 2 (see paragraph 20 and 38) and wherein the Listeria phagolysosomal domain is Hly and is encoded by a nucleic acid molecule selected from: (a) a nucleotide sequence comprising nucleotides 211-1722 as shown in SEQ ID No.1, (b) a nucleotide sequence which encodes the same amino acid sequence as the sequence from (a), and (c) a nucleotide sequence hybridizing under stringent conditions with the sequence wherein the stringent conditions washing for one hour 1 hour in 0.2×SSC and 0.1% SDS at 55° C., preferably at 62° C. and more preferably at 68° C. See paragraph 21-22.
Thus, the combination of the ‘118 claims and Grode et al renders prima facie obvious the instant claims.
With regards to claim 1, the recitation of “for administration as an immunotherapeutic agent to a subject suffering from recurrent non-muscle-invasive bladder carcinoma, as a second-line therapy, wherein the human subject has relapsed and/or in whom the bladder carcinoma has progressed after first-line immunotherapy with standard BCG, and wherein the bladder carcinoma recurrence is inhibited for a time period of at least 1 year” is an intended use of the claimed recombinant Mycobacterium cell. A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and those of the Grode et al to patentably distinguish the claimed invention from the recombinant Mycobacterium of the Grode et al. The recombinant Mycobacterium of the combination of the ‘’118 claims and Grode et al meets the structural limitations of the instant claims and therefore it is capable of performing the intended use recited in claim 1.
Applicant’s Argument:
Claim 1 of the present application is patentably distinct and directed to different claimed subject matter. As amended, claim 1 now requires treatment of recurrent non-muscle-invasive bladder carcinoma (NMIBC) as second-line therapy in a specifically defined patient group, namely, a human subject who has relapsed and/or in whom the bladder carcinoma has progressed after first-line immunotherapy with standard BCG, and further requires that the bladder carcinoma recurrence is inhibited for a time period of at least 1 year. Those limitations are not recited in claims 1-11 of Grode '118. In particular, Grode '118 does not claim treatment of recurrent NMIBC as such, does not claim the specifically selected group of subjects now recited in amended claim 1, and does not claim the therapeutic result that recurrence is inhibited for at least one year.
Further, Grode '118 does recite a recombinant Mycobacterium cell comprising the specified domains as fined in amended claim 1. The domain features were incorporated from claim 2, now canceled, which was not part of this rejection. Applicant further submits that even where Grode '118 claims administration to recurrent bladder carcinoma patients previously treated with standard BCG, the cited claims still do not recite the presently claimed second-line therapy for recurrent NMIBC in the specifically
amended patient subgroup together with the claimed one-year recurrence limitation.
Response to Applicant’s Argument
Applicants argument has been carefully considered but is not found persuasive. This is because claim 1 of the instant application is drawn to a product i.e. the recombinant Mycobacterium cell in combination with a carrier. The recitation of “for administration as an immunotherapeutic agent to a subject suffering from recurrent non-muscle-invasive bladder carcinoma, as a second-line therapy, wherein the human subject has relapsed and/or in whom the bladder carcinoma has progressed after first-line immunotherapy with standard BCG, and wherein the bladder carcinoma recurrence is inhibited for a time period of at least 1 year” is an intended use of the claimed recombinant Mycobacterium cell.
A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and those of the combination of the ‘118 claims and Grode et a; to patentably distinguish the claimed invention from the recombinant Mycobacterium of the combination of the‘118 claims and Grode et al. The recombinant Mycobacterium of the combination of the ‘118 claim and Grode et al meets the structural limitations of the instant claims and therefore it is capable of performing the intended use.
Claim 21, 26-31, 33-39 and 41-44 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4-11 of U.S. Patent No. 10,525,118 (‘118) in view of Grode et al. US 2020/0179502 June 11 2020.
Although the claims at issue are not identical, they are not patentably distinct from each other because:
Claim 21: The ‘118 claims disclose a method for the immunotherapy treat of bladder carcinoma (see claim 1). The ‘118 claim 4 and claim 6 disclose that non-invasive bladder cancer be a recurrent bladder cancer in who have been treated previously with standard BCG (first-line immunotherapy) – which corresponds to a subject suffering from recurrent non-muscle invasive bladder carcinoma which has relapsed and/or in whom the bladder carcinoma has progressed after a first-line immunotherapy with standard BCG, the method comprising administering to said subject as a second-line therapy a recombinant Mycobacterium cell, which is a urease C deficient, recombinant M. bovis BCG cell from strain Danish subtype Prague, which comprises a recombinant nucleic acid molecule encoding a fusion protein comprising:
a domain capable of eliciting an immune response; and
a Listeria phagolysosomal escape domain listeriolysin (Hly).
Claim 26: the administration is vesicular instillation into said human subject’s urinary bladder.
Claim 27-29, 30, 31: the human subject has previously undergone at least one unsuccessful first-line therapy of bladder carcinoma has i.e. patients with recurrent bladder carcinoma who have been treated previously with standard BCG (first line therapy or “another local treatment”. See claim 4.
Claim 33-35: The ‘118 claims disclose the immunotherapeutic agent is administered into the bladder according to a schedule involving weekly instillations during an induction phase, a first maintenance phase after about 3 months, a second maintenance phase after about 6 months and a third maintenance phase after about 12 months.
The ‘118 claims disclose the immunotherapeutic agent is administered into the bladder according to a schedule involving weekly instillations during an induction phase with 6 weekly instillations, a first maintenance phase after about 3 months with 3 weekly instillations, a second maintenance phase after about 6 months with 3 instillations and a third maintenance phase after about 12 months with 3 instillations.
Claim 36-37: The ‘118 claims disclose the recombinant Mycobacterium cell is administered at a dose of from 107 to 5 x 109 CFU per administration i.e. overlapping with the disclosed 106 to 1010 CFU per administration. Administering the recombinant cell at a dose of 2 x 109 CFU per administration would have been prima facie obvious to an ordinary skill in the art in view of the disclosure of the range 107 to 5 x 109 CFU per administration which encompasses 2 x 109 CFU per administration and thus would have been prima facie obvious to a person of ordinary skill in the art as of the effective filing date.
Claim 38: The ‘118 claims disclose disease recurrence is inhibited for at least 1 year as evidenced by maintenance phase after about 12 months. In addition, the method of claim 21 is disclosed and thus the same result should occur i.e. disease recurrence is inhibited for a time period selected from the group consisting of at least 1 year, at least 2 years, at least 3 years and at least 4 years.
Claim 39: The ‘118 claims disclose the method of claim 21 and thus the immunotherapy provides a disease- free time period selected from the group consisting of at least 1 year, at least 2 years, at least 3 years and at least 4 years.
Claim 41: the method of claim 21 is disclosed and thus disease recurrence is blocked for at least one further year in a subject without disease recurrence for a time period of 2 years after treatment starts.
Claim 42 - the method of claim 21 is disclosed and thus overall survival is increased compared to a human subject without treatment in a time period of at least 1 year.
Claim 43 - the method of claim 21 is disclosed and thus overall survival is increased compared to a human subject without treatment in a time period of at least 2 years, of at least 3 years or of at least 4 years.
Claim 44 - the method of claim 21 is disclosed and thus the need of cystectomy is reduced or avoided for a time period selected from the group consisting of at least a 1 year, at least 2 years, at least 3 years and at least 4 years.
The ‘118 claims do not disclose that the recombinant nucleic acid molecule is without a functional selection marker.
The ‘118 claims do not disclose that
the domain capable of eliciting an immune response comprises the amino acid sequence from aa. 41 to aa. 51 in SEQ ID NO: 2; and
does not disclose the Listeria phagolysosomal escape domain encoded by a nucleic acid molecule selected from:
(i) a nucleotide sequence comprising nucleotides 211-1722 as shown in SEQ ID
NO: 1,
(ii) a nucleotide sequence which encodes the same amino acid sequence as the sequence from (i), and
(iii) a nucleotide sequence hybridizing under stringent conditions with the sequence from (i) or (ii), wherein said stringent conditions comprise washing for one hour with 0.2 X or 1X SSC and 0.1% SDS at a temperature of 55-68°C.
Grode disclose a method for the immunotherapeutic treatment of non-muscle invasive bladder carcinoma (paragraph 35) that is recurrent in a subject wherein the subject is suffering said recurrent non-muscle invasive bladder carcinoma after standard BCG therapy is conducted (i.e. the carcinoma has relapsed or the bladder carcinoma has progressed after the first-line therapy with standard BCG (paragraph 15, 29 and example 3); the method comprising to said subject as a second line therapy:
a recombinant Mycobacterium bovis cell which is urease deficient M. bovis BCG cell from Danish subtype Prague (paragraph 11, 18, ) which comprises a recombinant nucleic acid molecule without a functional selection maker gene which expresses an Ag85B/Hly fusion protein (paragraph 38);
Wherein the nucleic acid molecule encodes a fusion polypeptide comprising:
(a) a domain capable of eliciting an immune response comprising the sequence from aa.41 to aa.51 in SEQ ID No.2, and
(b) a Listeria phagolysosomal escape domain encoded by a nucleic acid molecule selected from (i) a nucleotide sequence comprising nucleotides 211-1722 as shown in SEQ ID No.1, (ii) a nucleotide sequence which encodes the same amino acid sequence as the sequence from (i), and
(iii) a nucleotide sequence hybridizing under stringent conditions with the sequence from (i) or (ii), wherein said stringent conditions comprising washing for 0.2×SSC and 0.1% SDS at 55° C, preferably at 62° C. and more preferably at 68° C. See paragraph 22.
It would have been prima facie obvious to a person of ordinary skill in the art as of the effective filing date of the instant invention to have a domain capable of eliciting an immune response comprising the sequence from aa.41 to aa.51 in SEQ ID No.2 as the domain capable of eliciting an immune response and the Listeria phagolysosomal escape domain and encoded by a nucleic acid molecule selected from: (i) a nucleotide sequence comprising nucleotides 211-1722 as shown in SEQ ID NO: 1, (ii) a nucleotide sequence which encodes the same amino acid sequence as the sequence from (i), and (iii) a nucleotide sequence hybridizing under stringent conditions with the sequence from (i) or (ii), wherein said stringent conditions comprise washing for one hour with 0.2 X or 1X SSC and 0.1% SDS at a temperature of 55-68°C, as taught by Grode et al, thus resulting in the instant invention with a reasonable expectation of success.
The motivation to do so is that Grode et al disclose that a recombinant urease deficient recombinant M. bovis BCG cell from strain Danish which comprises a recombinant nucleic acid molecule without a functional selection marker (paragraph 38) encoding a fusion polypeptide comprising an Ag85B/Hly fusion protein can be used in the immunotherapy of non-muscle invasive bladder carcinoma, wherein the Ag85B is a domain capable of eliciting an immune response comprising the amino acid sequence from aa. 41 to aa. 51 in SEQ ID NO: 2 (see paragraph 20 and 38) and wherein the Listeria phagolysosomal domain is Hly and is encoded by a nucleic acid molecule selected from: (a) a nucleotide sequence comprising nucleotides 211-1722 as shown in SEQ ID No.1, (b) a nucleotide sequence which encodes the same amino acid sequence as the sequence from (a), and (c) a nucleotide sequence hybridizing under stringent conditions with the sequence wherein the stringent conditions washing for one hour 1 hour in 0.2×SSC and 0.1% SDS at 55° C., preferably at 62° C. and more preferably at 68° C. See paragraph 21-22.
Thus, the combination of the ‘118 claims and Grode et al renders prima facie obvious the instant claims.
Applicant’s Argument:
Claim 21 is patentable over claims 1-11 of Grode '118 because claims 1-11 of
Grode '118 do not recite one or more features recited in amended claim 21. For example, claims 1-11 of Grode '118 do not recite a method for treating "a subject suffering from recurrent non-muscle invasive bladder cancer which has relapsed and/or in whom the bladder carcinoma has progressed after a first-line immunotherapy with standard BCG in need thereof," wherein administration to said subject of the recombinant Mycobacterium cell is as "a second line therapy" with specifically defined domains, as recited in amended claim 21.
Applicant argues that Grode '502 does not disclose and would not have suggested a method for treating "a subject suffering from recurrent non-muscle invasive bladder cancer which has relapsed and/or in whom the bladder carcinoma has progressed after a first-line immunotherapy with standard BCG in need thereof," wherein administration to said subject of the recombinant Mycobacterium cell is as "a second line therapy" with specifically defined domains, as recited in amended claim 21.
Response to Applicant’s Argument
The combination of the ‘118 claims and Grode et al as set forth in the rejection above renders prima facie obvious the method of claim 21 including a method for treating "a subject suffering from recurrent non-muscle invasive bladder cancer which has relapsed and/or in whom the bladder carcinoma has progressed after a first-line immunotherapy with standard BCG in need thereof," wherein administration to said subject of the recombinant Mycobacterium cell is as "a second line therapy" and the combination of the ‘118 claims and Grode et al disclose the specifically defined domains for treating non-muscle invasive bladder cancer.
Claim 32 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 and 4-11 of U.S. Patent No. 10,525,118 (‘118) and Grode et al. US 2020/0179502 June 11 2020 as applied to 21, 26-31, 33-39 and 41-44 above further in view of Andrade et al. International Urology and Nephrology (2020) 52:1471-1476.
Although the claims at issue are not identical, they are not patentably distinct from each other because the combination of the ‘118 and Grode as set forth above, but does not disclose the subject is a smoker.
Andrade et al disclose that relapse (recurrent bladder cancer) after standard BCG treatment is a predictive for smokers. See title, abstract and under discussion p. 1474 column 1.
It would have been prima facie obvious to a person of ordinary skill in the art as of the effective filing date of the instant invention to have practiced the method of the combination of the ‘118 claims and Grode in smoker patients who have had a relapsed bladder cancer after standard BCG treatment, thus resulting in the instant invention with a reasonable expectation of success. The motivation to do so is that Andrade et al disclose that smokers being treated with standard BCG for bladder cancer are most likely to have a relapse (recurrence) of the bladder carcinoma.
Applicant’s Argument
Claim 32 depends on independent claim 21. Claim 32 is patentable over claims 1-11 of Grode '118 in view of Grode '502 and Andrade at least because Andrade fails to remedy the deficiencies of claims 1-11 of Grode '118 and Grode '502 set forth above with respect to independent claim 21. Accordingly, Applicant respectfully submits that claim 32 is patentable over claims 1-11 of Grode '118 in view of Grode '502 and Andrade and respectfully requests reconsideration and withdrawal of the rejection.
Response to Applicant’s Argument
Applicant’s argument has been carefully considered but is not found persuasive. The combination of the ‘118 claims and Grode et al renders prima facie obvious claim 21 for the reasons set forth above. The combination of the ‘118 claims and Grode et al and Andrade et al renders prima facie obvious claim 32.
Status of Claims
Claims 1, 21, 26-39 and 41-44 are rejected.
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).
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/OLUWATOSIN A OGUNBIYI/ Primary Examiner, Art Unit 1645
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