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 .
DETAILED ACTION
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Claims 1-6, and 11-18 have an effective filing date of 17MAY2022.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 6/12/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Election/Restriction
In the response filed on 1/2/2026, Applicant elected, without traverse:
Group I, claims 1-12
Status of Claims
Claims 1-6, and 11-18 are currently pending.
Claims 13-17 are withdrawn from further consideration by Examiner under 37 CFR 1.142(b) as being drawn to a non-elected invention.
Claims 1-5 are amended.
Claim 18 is new.
Claims 7-10 are canceled.
Rejections Withdrawn
The rejection filed under 35 U.S.C. 102 is withdrawn in view of Applicant’s amendments to claims.
The rejection filed under 35 U.S.C. 103 over Wyss-Coray et al and Zhang et al is withdrawn in view of Applicant’s amendments to claims.
The rejections filed under 35 U.S.C. 112(b) for indefiniteness is withdrawn in view of Applicant’s amendments to claims.
Rejections Maintained
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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 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 1-6, 11, and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Wyss-Coray et al (US 20200254075 A1, IDS 10/17/2023), Zhang et al (Alteration in the IL-2 signal peptide affects secretion of proteins in vitro and in vivo, J Gene Med 2005; 7: 354–365, IDS 10/17/2023) as applied to claims 1-8, and 11-12 above, and further in view of Higashi et al (US 20110195902 A1).
In regard to claim 1, Wyss-Coray et al teaches TIMP-2 polypeptides that include one or more modifications [0036]. Wyss-Coray et al further teaches modifications include but are not limited to: amide bond substitutions, amino acid substitutions, including of cysteine residues/analogues, cyclization, pegylation, etc [0036].
Wyss-Coray et al do not specifically teach the insertion of alanine before amino acid 27 of the native human TIMP-2 sequence. However, this deficiency is made up by Higashi et al.
Higashi et al teaches coordination of the α-amino group of the N-terminal Cys 1 of TIMP-2 to the zinc ion at the activity center of MMP is important for the inhibitory activity of TIMP-2; when this α-amino group is chemically modified, or when one alanine residue is added to the N-terminus of TIMP-2 (see [0095]), the result is an MMP-2 inhibitor - “when APP-IP is added to the N-terminus of TIMP-2, TIMP-2's MMP inhibitory activity with low specificity is lost and, at the same time, interaction between APP-IP and the catalytic site of MMP-2 is enhanced, yielding an inhibitor with high affinity and specificity for MMP-2.” [0086].
Wyss-Coray et al do not specifically teach modifications to the signaling protein. However, this deficiency is made up in the teachings of Zhang et al.
Zhang et al teaches the modification of the signal peptide [Abstract]. Zhang et al further teaches the modification are to increase therapeutic levels of secreted proteins [Abstract].
One of ordinary skill, before the effective filing date, would have been motivated to combine Wyss-Coray’s method of modifying TIMP-2 polypeptide, with Zhang’s method of modifying the signaling protein to one that is not present in the native protein, with Higashi’s method of adding an alanine to the N-terminus of TIMP-2. The idea of combining them flows logically from their having been individually taught in the prior art (MPEP 2144.06). Combining prior art elements according to known methods to yield predictable results is an exemplary rationale for a prima facie case of obviousness. MPEP2143. It would have been prima facie obvious to combine Wyss-Coray, Zhang, and Higashi’s methods for a recombinant TIMP-2 protein comprising a signal peptide not present in native human TIMP-2 and inserting an alanine in to the N-terminus, because the result is an MMP-2 inhibitor. This would be an advantageous modification, because “[m]atrix metalloproteinases (MMPs) are proteolytic enzymes having high degradation activity against extracellular matrix proteins and are considered to support cell migration during cancer invasion and metastasis.” See [0002].
In regards to claim 2, Zhang et al teaches the modification of the signal peptide [Abstract]. Zhang et al further teaches the modification are to increase therapeutic levels of secreted proteins [Abstract].
In regards to claim 3, Zhang et al further teaches a signal protein from IL-2 for cells MDA-MB-435 [Abstract]. Zhang further teaches both modified and wild-type signal peptide [Abstract].
In regard to claim 4, Wyss-Coray et al further teaches the addition of a Fc region [0056].
In regards to claim 5, Wyss-Coray et al further teaches attaching an Fc region to the polypeptide [0056]. Wyss-Coray et al further teaches an Fc attachment has been shown to increase the systemic half-life of bio-pharmaceuticals [0056]. Furthermore, one of ordinary skill in the art would have been motivated to modify the Fc region [0056], and one of ordinary skill in the art would appreciate that there are four IgG subclasses, IgG1-IgG4.
In regards to claim 6, Wyss-Coray et al further teaches the TIMP-2 polypeptide also includes fragments thereof which exhibits the desired TIMP-2 activity [0031].
In regards to claim 11, Wyss-Coray et al further teaches the use of nucleic acid encoding the protein to be produced in cells [0051].
In regards to claim 12, Wyss-Coray et al further teaches the use of nucleic acids in vectors [0063].
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Wyss-Coray et al (US 20200254075 A1, IDS 10/17/2023), Zhang et al (Alteration in the IL-2 signal peptide affects secretion of proteins in vitro and in vivo, J Gene Med 2005; 7: 354–365, IDS 10/17/2023), Higashi et al (US 20110195902 A1) as applied to claims 1-6, 11, and 12 above, and further in view of Miyazaki et al (US 6534635 B1).
The teachings of Wyss-Coray et al, Zhang et al, and Higashi et al are discussed above.
Wyss-Corey et al does not specifically teach SEQ ID NO: 36. However, this deficiency is made up in the teachings of Miyazaki et al.
In regard to claim 18, Miyazaki et al teaches a modified TIMP [Abstract]. Miyazaki et al further teaches TIMP-2. A comparison of instant SEQ ID NO: 36 and TIMP-2 of Miyazaki et al is shown below.
Instant SEQ ID NO: 36 and TIMP-2 of Miyazki et al.
Query Match 98.8%; Score 1179.5; Length 220;
Best Local Similarity 99.5%;
Matches 220; Conservative 0; Mismatches 0; Indels 1; Gaps 1;
Qy 1 MGAAARTLRLALGLLLLATLLRPADAACSCSPVHPQQAFCNADVVIRAKAVSEKEVDSGN 60
||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||
Db 1 MGAAARTLRLALGLLLLATLLRPAD-ACSCSPVHPQQAFCNADVVIRAKAVSEKEVDSGN 59
Qy 61 DIYGNPIKRIQYEIKQIKMFKGPEKDIEFIYTAPSSAVCGVSLDVGGKKEYLIAGKAEGD 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 60 DIYGNPIKRIQYEIKQIKMFKGPEKDIEFIYTAPSSAVCGVSLDVGGKKEYLIAGKAEGD 119
Qy 121 GKMHITLCDFIVPWDTLSTTQKKSLNHRYQMGCECKITRCPMIPCYISSPDECLWMDWVT 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 120 GKMHITLCDFIVPWDTLSTTQKKSLNHRYQMGCECKITRCPMIPCYISSPDECLWMDWVT 179
Qy 181 EKNINGHQAKFFACIKRSDGSCAWYRGAAPPKQEFLDIEDP 221
|||||||||||||||||||||||||||||||||||||||||
Db 180 EKNINGHQAKFFACIKRSDGSCAWYRGAAPPKQEFLDIEDP 220
One of ordinary skill, before the effective filing date, would have been motivated to combine Wyss-Coray’s method of modifying TIMP-2 polypeptide, with Zhang’s method of modifying the signaling protein to one that is not present in the native protein, with Higashi’s method of adding an alanine to the N-terminus of TIMP-2, with Miyazaki’s TIMP-2. Te idea of combining them flows logically from their having been individually taught in the prior art (MPEP 2144.06). Combining prior art elements according to known methods to yield predictable results is an exemplary rationale for a prima facie case of obviousness. MPEP2143. It would have been prima facie obvious to combine Wyss-Coray, Zhang, Higashi, and Miyazaki’s methods for a recombinant TIMP-2 comprising SEQ ID NO: 36, because the resultant invention would function as an MMP-2 inhibitor.
Applicant’s Arguments:
Applicant traverses the rejections.
Zhang does not relate to TIMP-2. Zhang discloses modifications to the IL-2 signal peptide to improve secretion of recombinant proteins (using endostatin and placental alkaline phosphatase as examples) with the aim of overcoming limitations of current gene therapy due to poor efficiency of transfection and low production of the therapeutic protein. Nothing in Zhang suggests that TIMP-2 is or can also be used.
Regarding the second rejection, Applicant respectfully submits that the combination of Wyss-Coray with Higashi to arrive at claim 1 as amended is not properly founded by the Examiner. In fact, Higashi teaches exactly the opposite of the present application. Specifically, Higashi teaches how to improve MMP inhibitory activity of TIMP-2 by adding a beta-amyloid peptide to the N-terminal of the TIMP-2 protein with a linker in between. See Higashi, Figs. 1 and 2 and paragraph [0009].
Specifically, the present application achieves the effect of reducing the inhibitory effect of TIMP-2 over MMPs such that the recombinant TIMP-2 protein retains the ability to improve cognitive performance, while reducing unwanted side effects such as musculoskeletal pain and inflammation associated with inhibition of MMP.
While Higashi discloses a report where one alanine residue was appended to the N-terminus of TIMP-2, this report does not indicate that the alanine residue is inserted before amino acid position 27 in the precursor TIMP-2 protein.
Examiner’s Response:
Applicant states, “Zhang does not relate to TIMP-2.”.
Examiner agrees, Zhang et al teaches modification of the signal peptide on the protein level [Left column, Discussion, pg. 363]. Zhang et al further teaches a rich diversity of signal peptides a method to screen naturally occurring signal peptides for their ability to increase protein secretion [Left column, Discussion, pg. 363].
One of ordinary skill in the art, would recognize that Zhang et al teaches a method of modification of signal peptides of various proteins, and uses IL-2 as an example.
Applicant states, “Higashi teaches how to improve MMP inhibitory activity of TIMP-2 by adding a beta-amyloid peptide to the N-terminal of the TIMP-2 protein with a linker in between.”.
MPEP 2143.01 (I)states that
The disclosure of desirable alternatives does not necessarily negate a suggestion for modifying the prior art to arrive at the claimed invention. In In re Fulton, 391 F.3d 1195, 73 USPQ2d 1141 (Fed. Cir. 2004), the claims of a utility patent application were directed to a shoe sole with increased traction having hexagonal projections in a "facing orientation." 391 F.3d at 1196-97, 73 USPQ2d at 1142. The Board combined a design patent having hexagonal projections in a facing orientation with a utility patent having other limitations of the independent claim. 391 F.3d at 1199, 73 USPQ2d at 1144. Applicant argued that the combination was improper because (1) the prior art did not suggest having the hexagonal projections in a facing (as opposed to a "pointing") orientation was the "most desirable" configuration for the projections, and (2) the prior art "taught away" by showing desirability of the "pointing orientation." 391 F.3d at 1200-01, 73 USPQ2d at 1145-46. The court stated that "the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." Id. In affirming the Board’s obviousness rejection, the court held that the prior art as a whole suggested the desirability of the combination of shoe sole limitations claimed, thus providing a motivation to combine, which need not be supported by a finding that the prior art suggested that the combination claimed by the applicant was the preferred, or most desirable combination over the other alternatives. Id. See also In re Urbanski, 809 F.3d 1237, 1244, 117 USPQ2d 1499, 1504 (Fed. Cir. 2016).
Higashi et al does not criticize, discredit, or otherwise discourage the insertion of alanine before amino acid 27 of the native human TIMP-2 sequence.
Applicant states, “Higashi discloses a report where one alanine residue was appended to the N-terminus of TIMP-2, this report does not indicate that the alanine residue is inserted before amino acid position 27 in the precursor TIMP-2 protein”.
The addition of an N-terminal alanine suggests that said alanine may be placed at the N-terminus, which would be close to or located at position 1.
New Rejections
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 1-6, 11-12, and 18 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 recites, “i) an alanine insertion before amino acid number 27 of the native TIMP2 protein precursor”, but Applicant has not defined what the native TIMP2 protein precursor is, for example, by indicating a particular amino acid sequence for a native TIMP2 protein.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DENNIS JOHN SULLIVAN whose telephone number is (571)272-0509. The examiner can normally be reached Mon - Fri: 7:30AM - 4:30PM.
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, Samira Jean-Louis can be reached at (571) 270-3503. 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.
/DENNIS J SULLIVAN/Examiner, Art Unit 1642
/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642
Prosecution Insights