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 .
Claim Status
The preliminary amendment filed 09/25/23 is acknowledged. Claims 1-21 are cancelled. Claims 1-38 are new. The response to the restriction requirement filed 06/22/26 is acknowledged. Applicant elects Group I (claims 22-35) without traverse. Claims 36-38 are withdrawn. Claims 22-38 are pending. Claims 22-35 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 – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Specifically, FIG. 42. Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code [see, at least, pars. 393, 434, and 651 of the specification]; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Rejections - 35 USC § 112b
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 22-35 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 22 recites a method for determining a level of circulating TGFβ in a blood sample but does not recite measuring TGFβ or any other step that produces a TGFβ level. The only recited measurement is PF4, which the specification describes as a quality control marker for platelet activation rather than as a measurement of TGFβ [see instant specification, p. 236, par. 896]. Thus, it is unclear whether the claim requires measuring TGFβ in addition to PF4 or merely performing the recited steps. To advance compact prosecution, the claim is interpreted such that determining a level of TGFβ is a required step of the claimed method as this appears consistent with the specification [see instant specification, p. 236, par. 896]. Claims 23-35 are included in this rejection because they explicitly or implicitly require the method of claim 22 but do not correct the indefiniteness.
Therefore, claims 22-35 are rejected under 35 U.S.C. 112(b) as indefinite.
Claim Rejections - 35 USC § 112a
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 26 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 26 recites the anticoagulant citrate-theophylline-adenosine-dipyridamole (CTAD) comprising ingredients in specific concentrations. The specification, however, does not provide an example demonstrating preparation or use of an anticoagulant having these claimed concentrations. While the examples teach that the inventors used CTAD, the art recognizes that CTAD conventionally comprises the same ingredients in the following concentrations: 0.11 mol/L citric acid, 15 mmol/L theophylline, 3.7 mmol/L adenosine, and 0.198 mmol/L dipyridam ole, pH 5.0 [see Jern et al., p. 3378, col. 1, par. 2, DiatubeH, also known as CTAD]. Accordingly, the disclosure fails to reasonably convey that the inventors had possession of the claimed formulation.
Therefore, claim 26 is rejected under 35 U.S.C. 112(a) for lack of written description.
Claims 29-35 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 TGFβ1 antibodies [see instant specification par. 7], does not reasonably provide enablement for all possible TGFβ inhibitors. 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.
Datta et al. teaches that while TGFβ is an attractive target, various studies have revealed serious toxicities associated with systemic inhibition of TGFβs in vivo because of off target effects and notes that despite lines of direct and indirect evidence pointing to the importance of TGFβ signaling in the progression of diseases, there are no TGFβ therapeutics available in the market to date which are deemed safe and efficacious [see col. 1, par. 6, through col. 2, par. 1]. This supports the conclusion that the effects of TGFβ inhibition were not sufficiently predictable such that the limited disclosure of the instant application, which comprises the use of TGFβ1 isoform specific antibodies, would enable a person having ordinary skill in the art to use the invention across the full scope of claim 29 without undue experimentation. Claims 30-35 are included in this rejection for requiring the method of claim 29.
Therefore, claims 29-35 are rejected under 35 U.S.C. 112(a) for lack of enablement.
Claim Rejections - 35 USC § 103
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 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.
Claims 22, 23, 27, and 28 are rejected under 35 U.S.C. 103 as being unpatentable over O’Brien et al. in view of Kong et al. (2017; herein Kong1).
Claims 22, 23, 27, and 28 are drawn to a method of determining a level of TGFβ in a sample.
O’Brien et al. teaches that accurate measurement of circulating TGFβ is complicated by the high TGFβ content of platelets that can be released during sample collection and processing [see p. 564, col. 1, par. 2]. O’Brien et al. teaches a method for determining TGFβ1 level in a blood sample comprising collecting blood in CTAD containing tubes [see p. 564, col. 2, par. 2] (instant claim 22) and teaches that CTAD reduces platelet activation relative to the conventional plasma collection anticoagulant ethylenediaminetetraacetic acid (EDTA) [see p. 567, col. 1]. O’Brien et al. further teaches centrifuging the blood for 15 minutes at 2500 ×g, transferring the central portion of the plasma to a second tube, and centrifuging a second time for 15 minutes at 2500 ×g [see p. 564, col. 2, par. 2] (instant claims 22 and 23). The samples are then analyzed for TGFβ and PF4 using enzyme immunoassays [see p. 565, col. 1, par. 2] (instant claim 22). O’Brien et al. teaches that the samples underwent initial acidification steps immediately prior to TGFβ analysis to activate latent TGFβ into an immunoreactive form [see p. 564, col. 2, par. 3], thereby measuring latent TGFβ1 (instant claim 28).
O’Brien et al. does not teach or suggest that the samples be processed at 2-8° C.
Kong1 teaches a method for determining TGFβ1 level in a blood sample comprising collecting blood samples in tubes containing the anticoagulant EDTA [see p. 626, col. 2, par. 4], placing the tubes on ice, centrifuging the tubes at 2500-3000 ×g for 30 minutes at 4° C [see p. 627, col. 1] and measuring both TGFβ1 and PF4 levels via enzyme-linked immunosorbent assay (ELISA) [see p. 627, col. 2]. Kong1 teaches that PF4 is a reliable marker for platelet contamination/degradation [see p. 632, col. 1, par. 2] which are terms used synonymously with “activation” throughout the text [for example, see p. 626, col. 2, par. 2]. Kong1 teaches that blood samples can show increased PF4 and TGFβ1 from the samples being left at room temperature, from an extended delay in processing, or from an inappropriate centrifugal force or duration [see p. 632, col. 1, par. 1]. Kong1 specifically notes that samples should always be stored on ice and never left at room temperature [see p. 633, col. 1, par. 3] (instant claim 22).
It would have been obvious to modify the sample processing method of O’Brien to perform the processing and centrifugation at 2-8° C because O’Brien et al. teaches that platelet activation is a consequence of improper sample collection and/or preparation while Kong1 teaches that processing samples on ice and at 4° C are critical to reducing platelet activation. The combination of these teachings would have constituted using a known sample-processing condition for its known purpose in an established method and would therefore have provided a reasonable expectation of success. Regarding dependent claim 27, the claim recites only intended use without introducing any active steps into the method and is therefore rejected along with independent claim 22 (instant claim 27).
Therefore, claims 22, 23, 27, and 28 are rejected under 35 U.S.C. 103.
Claims 22, 24, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over O’Brien et al. in view of Kong et al. (2017; herein Kong1), and in further view of Dhurat et al.
Claims 22, 24, and 25 are drawn to a method of determining a level of TGFβ in a sample.
For the purposes of examination, the examiner interprets dependent claims 24 and 25 as requiring the selection of multiple centrifugation steps as recited in claim 22.
The teachings of O’Brien et al. and Kong1 are discussed above.
Dhurat et al. teaches that centrifugation conditions used for processing blood are subject to optimization, specifically disclosing various centrifugation protocols that optimize variables including spin force, time, and range of acceleration [see p. 192, col. 1, par. 4; see p. 193; see p. 192, Table 2]. Dhurat et al. teaches that these variables are critical to optimizing platelet samples and notes that each laboratory must standardize its own protocol [see p. 194, col. 1, par. 4]. Most of the protocols disclosed by Dhurat et al. comprise a first spin at a lower force than the second spin [see p.192, Table 2] and Dhurat et al. teaches that the dual spin method with a faster second spin is helpful in obtaining optimum platelet concentrate [see p. 196, col. 1, par. 1].
In view of these teachings, it would have been obvious to a person having ordinary skill in the art to optimize the speed and durations of O’Brien’s modified method comprising two 2500 ×g centrifugations. Dhurat et al. specifically teaches that each protocol should be optimized, teaches that a softer first spin provides good yield, and provides several protocols disclosing that a less forceful and shorter first spin produces good platelet yield. As such, modifying the method which already comprises two 15-minute 2500 ×g spins such that it comprises a slower first spin (instant claim 24) or a 10 minute first spin and a 20 minute second spin (instant claim 25(ii)) would have been a matter of routine optimization and constituted a predictable variation of the known centrifugation parameters, absent unexpected results.
Therefore, claims 22, 24, and 25 are rejected under 35 U.S.C. 103.
Claims 29-35 are rejected under 35 U.S.C. 103 as being unpatentable over O’Brien et al. in view of Kong et al. (2017; herein Kong1), and in further view Datta et al. (US Patent 11130803) and Kong et al. (1996; herein referred to as Kong2).
Claims 29-35 are drawn to a method of treating cancer in a subject.
The teachings of O’Brien et al. and Kong1 are discussed above.
The combination of these references does not teach or suggest a method of treating cancer with a TGFβ inhibitor.
Datta et al. teaches administration of Ab6, which is a TGFβ1-sepcific inhibitory antibody [see col. 98, par. 3; see Table 1] (instant claim 29), to MBT-2 (bladder cancer) [see col. 247, par. 2] and CloudmanS91 (melanoma) [see col. 249, par. 5] solid tumor-bearing mice (instant claims 33 and 34) and demonstrates that the treatment in combination with an anti-PD-1 antibody (instant claims 30 and 31), delayed tumor growth, produced tumor regressions, and produced increased survival [see col. 248, par. 4-6; see col. 249, par. 5]. Datta et al. teaches that the disclosed antibodies, which includes Ab6, are useful for the treatment of gastric cancer [see col. 163, par. 2] (instant claim 35) and may be administered with a PARP inhibitor [see col. 176, par. 3] (instant claim 32).
Kong2 teaches monitoring circulating TGFβ1 levels in lung cancer patients before, during, and after radiotherapy [see abstract] (instant claim 29). Kong2 teaches that plasma TGFβ1 levels were elevated before treatment, reduced during treatment, and noted that TGFβ1 levels at follow up correlated to disease status [see abstract]. Kong2 teaches that TGFβ1 may be a useful plasma tumor marker with which to monitor the results of lung cancer treatment [see p. 57, par. 5].
It would have been obvious to combine these teachings and utilize the modified method of O’Brien et al. with the cancer treatment method of Datta et al. and the repeated testing method of Kong2. More specifically, given that Datta et al. teaches that TGFβ inhibition can produce an antitumor effect in a subject, measuring the levels of TGFβ before and after treatment would have been a logical and predictable means of assessing the subject’s response to administering a TGFβ inhibitor. Kong2 supports this rationale, teaching that monitoring TGFβ1 levels is a useful method of monitoring treatment status. Furthermore, it would have been obvious to administer an additional dose of the inhibitor if TGFβ levels were not sufficiently low as the treatment is dependent on suppression of TGFβ. The limitation of “wherein the increase is at least 1.5-fold” recites an expected result without introducing any active steps into the method and is therefore interpreted as an inherent property.
Regarding claim 32, it would have been obvious to administer a PARP inhibitor in a combination therapy with the TGFβ inhibitor because Datta et al. specifically contemplates the coadministration of these agents and PARP inhibitors were known therapeutic agents for the treatment of cancer.
Therefore, claims 29-35 are rejected under 35 U.S.C. 103.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Tirone D Johnson whose telephone number is (571)272-1256. The examiner can normally be reached M-F, 9-5 ET.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Stucker can be reached at (571)272-0911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/TIRONE D. JOHNSON/ Examiner, Art Unit 1675
/JEFFREY STUCKER/ Supervisory Patent Examiner, Art Unit 1675
Prosecution Insights