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 .
Status of Claims
Claims 1-3, 6, 13, 17, 30-34 and 38-39 are pending following the Reply filed 11/20/2025. Claims 2, 10 and 12 have been cancelled. Claims 1, 3, 6, 13 and 17 have been amended without adding new matter. Claims 30-31, 33-34 and 38-39 are withdrawn. Claims 1, 3, 6, 13, 17 and 32 have been examined on the merits.
Information Disclosure Statement
The information disclosure statements (IDS) filed on 11/20/2025 has been considered by the examiner.
Withdrawn
The objection to the drawings is withdrawn in light of the replacement drawings filed 11/20/2025.
Any rejection of claims 2, 10 or 12 is moot because the claims are cancelled.
The rejections of claims 3, 13 and 17 under 35 U.S.C. 112(b) have been withdrawn in light of the amendments.
The rejections of claims 1, 6, 13 and 32 under 35 U.S.C. 112(a) for failing to meet the written description requirement has been withdrawn in light of the amendments. In particular, the limitations of cancelled claim 2, which was free of this rejection, have been incorporated into amended claim 1, from which claims 6, 13 and 32 depend.
Claim Objections
Claim 1 is objected to because of the following informalities: Please provide the unabbreviated name for each of the proteases, “MMP12” in line 7, “CTSD” in line 9, and “CTSL” in line 12 (i.e., as recited in the instant specification at pg. 2, lines 13-15). For example, “MMP12” should be amended to recite “matrix metalloproteinase-12 (MMP12)”. Appropriate correction is required.
Claims 1 and 17 are objected to because of the following informalities: Claim 1 recites “a peptidase domain” in line 4, whereas claim 17 recites “the active peptidase domain” in lines 3, 6, 9 and 12. It is clear that “the active peptidase domain” recited in claim 17 refers to the “peptidase domain” of claim 1. Please amend one of the claims to recite the same phrasing when referring to this element. For example, claim 1 may be amended to recite “an active peptidase domain” or claim 17 may be amended to recite “the . Appropriate correction is required.
Maintained rejections and new rejections necessitated by Amendment
Claim Rejections - 35 USC § 103
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
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 1, 3, 6, 13, 17 and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Franano et al., US 20090162343 A1 (previously cited), hereafter “Franano”, and further in view of Becker et al., WO 2018232273 A1 (previously cited), hereafter “Becker”.
Regarding claim 1, Franano teaches that there is no known commercially viable means of producing biologically active elastase in sufficiently pure form and in sufficient quantities for clinical applications (see pg. 1, para. [0004]), and there is a need in the art for recombinant manufacturing methods that allow the generation of therapeutic amounts of biologically active pharmaceutical grade elastases, preferably avoiding a trypsin activation step which may reduce some of the beneficial effects of elastase treatment (see pg. 1, para. [0006]). Franano teaches that preferred elastases are type I pancreatic elastases, e.g., human type I pancreatic elastase and porcine type I pancreatic elastase (see pg. 1, para. [0011]) which are serine proteases. Franano teaches such elastases are often expressed as preproproteins containing a signal peptide, an activation peptide, and a mature, active protein (see pg. 1, para. [0005]). Franano also teaches the proelastase protein comprises a cleavage domain or cleavage site in the region spanning the junction between the elastase propeptide and the mature elastase protein (see pg. 2, para. [0024]), corresponding to an activation peptide, wherein the proprotein is cleaved to generate the active, mature protein (see pg. 7, para. [0036]). Franano teaches that for recombinant expression, an inactive precursor (i.e., propeptide) may be expressed instead of the mature active enzyme to circumvent damage to the cell that expresses it (see pg. 1, para. [0005]).
In view of the instant specification, the “peptidase domain” is the “active serine protease domain” of the proprotein (see, e.g., pg. 2, line 23). Hence, the “mature, active protein” taught by Franano meets the limitation of a “peptidase domain”. Furthermore, Franano teaches the proelastase to comprise the signal sequence, activation peptide, cleavage domain/site, and mature elastase protein, respectively, in a C-terminal to N-terminal orientation (see pg. 2, paras. [0014]-[0024] and FIG. 2). Franano also teaches that pre and pro sequences of the elastase proteins are typically not native (i.e., heterologous) to the elastase genes encoding the mature elastase proteins (see pg. 2, para. [0012]).
Franano does not teach the serine protease proprotein wherein the cleavage site is selected from SEQ ID NOs 8-10, 11-12 or 14-16.
Becker teaches that certain serine proteases have the capacity to kill a broad range of cancer cells while minimally affecting the viability of non-cancer cells, including cathepsin G (CTSG), proteinase 3 (PRTN3), porcine pancreatic elastase (PPE), and human neutrophil elastase (ELANE) (see pg. 8, paras. [0019]-[0020]). Becker teaches therapeutic compositions comprising neutrophil-secreted factors that are advantageous over neutrophils and/or neutrophil stimulating or recruiting agents for at least three reasons: (1) by delivering the anticancer agents (i.e., polypeptides) of the disclosure one has better control over dosing regimens and can therefore better modulate efficacy and potential toxicity of the therapeutic; (2) substantial evidence suggests that tumors can reprogram the anti-tumor neutrophils in early stage cancer to a pro-tumor phenotype and thus promote metastasis; and (3) keeping neutrophils alive before transfusion as well as the development of Graft-versus-Host disease are currently a challenge (see pg. 3, para. [0011]). Becker teaches that one such neutrophil-secreted factor having cancer specific killing capability is human neutrophil elastase (ELANE) (see pg. 3, para. [0012]). Becker teaches that an ELANE polypeptide can be modified by including heterologous peptide sequences at the amino (N) terminus of the polypeptide (see pg. 6, lines 13-16). Becker teaches the neutrophil elastase (ELANE) or variant thereof has an amino acid sequence represented by SEQ ID NO: 2 (see pg. 11, para. [0023]). As shown in the following alignment, Becker’s SEQ ID NO: 2 (bottom) contains a sequence from amino acid residues 27 to 34 that is identical to the “heterologous protease cleavage site” of instant SEQ ID NO: 13 (top):
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However, the instant claim has been amended to no longer recite the limitation, wherein “the heterologous protease cleavage site is SEQ ID NO: 13”.
Nevertheless, the following alignment compares the same region of Becker’s SEQ ID NO: 2 (bottom), from residues 27 to 34, with instant SEQ ID NO: 9 (top):
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131
643
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Franano teaches that the region spanning the cleavage domain of the proprotein comprises 8 amino acid residues, Xaa1 (P5) to Xaa8 (P’3) (see pg. 15, para. [0138]). Franano teaches the cleavage domain, wherein Xaa1 is glycine (G) or alanine (A), Xaa2 is alanine (A) or proline (P), Xaa3 is alanine (A) or leucine (L), Xaa4 is isoleucine (I) or glycine (G), Xaa5 is valine (V) or alanine (A), Xaa6 is valine (V) or alanine (A), and Xaa7 is glycine (G) (see pgs. 15-16, paras. [0139]-[0145]). Hence, Franano teaches that the cleavage domain may comprise a sequence according to G-A-A-G-V-V-G-X. Franano discloses that to obtain a variant proenzyme capable of auto-activation, thereby eliminating the need for trypsin activation, a variety of elastase cleavage domain variant vectors were constructed and analyzed in small-scale culture and conversion experiments (see pg. 38, para. [0384]). Note that all of the cleavage domain variants in Table 4 (pg. 38) have a Gly (G) at position P’3 (Xaa8). Hence, in view of Franano’s disclosure, one would have reasonably arrived at a cleavage domain sequence of G-A-A-G-V-V-G-G by following Franano’s teachings and examples. As shown in the following alignment, this sequence (bottom) is identical to instant SEQ ID NO: 9 (top):
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133
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It would have been obvious at the time of filing for a person of ordinary skill in the art to have arrived the claimed invention by combining the teachings of Franano and Becker, because both references teach methods and compositions using therapeutic elastases. One would have been particularly motivated to do so, because Becker teaches that compositions comprising human neutrophil elastase (ELANE) can be an effective treatment for killing a broad range of cancer cells. Further, one would have recognized from Franano the advantages of providing the therapeutic elastase as an inactive precursor (proprotein) which can effectively be used to control activation of the protease by keeping it inactive until it is under the desired conditions. As both references teach heterologous peptides can be included in the N-terminus of the elastase, such as the signal and activation peptides of the proelastases taught by Franano, one could have combined these teachings to produce a modified elastase that includes a cleavage site that is only cleavable under the conditions desired for activation of the enzyme. Further, Franano discloses functional variants of the cleavage domain and sufficient guidance for one to have arrived at the heterologous cleavage site of the claim. Furthermore, there would have been a reasonable expectation of success, because Becker teaches that certain elastases, such as human neutrophil elastase (ELANE) and porcine pancreatic elastase (also taught by Franano), are effective for killing cancer cells. Hence, the combination would have been readily apparent and deemed to be a mere (A) combining of prior art elements according to known methods to yield predictable results (see MPEP 2143(I): Rationales to support rejections under 35 U.S.C. 103). Furthermore, it is well within the ordinary skill in the art to design proproteins with cleavage sites specific to certain proteases known to recognize and bind to certain cleavage domain sequences.
Regarding claim 3, Becker teaches the neutrophil elastase (ELANE) or variant thereof has an amino acid sequence represented by SEQ ID NO: 2. As shown in the following alignment, instant SEQ ID NO: 2 (top) is identical to Becker’s SEQ ID NO: 2 (bottom):
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423
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Regarding claim 6, Franano teaches the cleavage domain of the proprotein, wherein Xaa1 is glycine (G) or alanine (A), Xaa2 is alanine (A) or proline (P), Xaa3 is alanine (A) or leucine (L), Xaa4 is isoleucine (I) or glycine (G), Xaa5 is valine (V) or alanine (A), Xaa6 is valine (V) or alanine (A), Xaa7 is glycine (G), and Xaa8 is glycine (G), as discussed regarding claim 1. Hence, Franano teaches that the cleavage domain may comprise a sequence according to A-P-L-G-A-A-G-G. As shown in the following alignment, this sequence (bottom) differs by a single amino acid residue compared to instant SEQ ID NO: 14 (top):
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110
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However, Franano teaches that the recognition sequence comprises amino acid residues P3 through P1 (see pg. 2, para. [0018]; Fig. 2), which correspond to positions 3 through 5 above, and the cleavage bond is located between P1 and P1’ (see Fig. 2) which is between positions 5 and 6 above. Franano teaches that the variants may contain conservative amino acid substitutions at non-essential amino acid residues (see pg. 17, para. [0166]) and identifies the substitution of proline to leucine to be a conservative substitution of two nonpolar side chains (see pg. 17, para. [0168]). Therefore, a person of ordinary skill would have had a reasonable expectation that substituting a non-essential proline (P) with a leucine (L) at this position would have resulted in a functional variant, because this position is outside the elastase recognition sequence and is further separated from the cleavage bond by said recognition sequence. Hence, a person of skill would have recognized there to be a finite number of identified, predictable solutions when constructing variants and could have arrived at the claimed sequence through no more than routine optimization. Furthermore, Applicant’s Examples do not disclose any embodiments involving instant SEQ ID NO: 14, and therefore there is no evidence of unexpected results to weigh against the evidence supporting prima facie obviousness. See MPEP 716.02(c). Furthermore, it is well within the ordinary skill in the art to optimize a cleavage domain by making conservative substitutions to amino acid residues that are non-essential to the functioning (e.g., activation) of a proprotein.
Regarding claim 13, Franano teaches that the proprotein is cleaved at the protease cleavage site to generate an active, mature protein or “active peptidase domain”, as discussed above. Because Franano teaches that the proprotein is inactive in its proprotein form (as previously discussed), one of ordinary skill would have expected the “active peptidase domain” to have increased serine protease activity relative to the proprotein. Furthermore, where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). In this case, there is no further structure recited for the modified serine protease proprotein in the present claim, and the active peptidase domain having increased serine protease and/or cancer cell-killing activity is an inherent property that would necessarily be present in the modified serine protease proprotein of claim 1. Because the limitations of the claimed product are necessarily present in the prior art combination, the functional limitations of the asserted claim are inherently met by the combination of references. See MPEP 2112. Hence, claim 13 is obvious for the same reasons discussed regarding claim 1.
Regarding claim 17, as shown in the following alignment, amino acid residues 30-247 of instant SEQ ID NO: 2 (top) are identical to the same region of Becker’s SEQ ID NO: 2 (bottom):
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86
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Regarding claim 32, Becker teaches pharmaceutical compositions comprising the human neutrophil elastase (ELANE) and a pharmaceutically acceptable carrier (see pg. 46, para. [0120]).
Response to Arguments
Regarding the rejections under 35 U.S.C. 103 in view of Franano and Becker, Applicant argues that the amended claims delete reference to SEQ ID NO: 13. In the least because the combination of cited references fails to teach or suggest each claimed feature, that is, a serine protease comprising a heterologous protease cleavage site selected from SEQ ID NOs: 8-12 or 14-16, Applicant submits that a prima facie case of obviousness has not been established.
Applicant’s arguments have been fully considered but they are not persuasive. As discussed under the present rejection, Franano teaches the modification of wildtype cleavage domains to produce variants. As discussed regarding claim 1, it would have been prima facie obvious for a person of skill to have arrived a sequence identical to instant SEQ ID NO: 9 by merely following Franano’s express teachings and examples. As discussed regarding claim 6, a person of skill could have arrived at a cleavage domain according to instant SEQ ID NO: 14 by merely following Franano’s express teachings and examples, and further, through no more than routine optimization (i.e., the conservative substitution of a single non-essential amino acid residue, as evidenced by Franano’s disclosure). See the present rejections under 35 U.S.C. 103 for further discussion.
Conclusion
No claims are allowed.
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.
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/DENNIS IGNATIUS ARMATO JR/Examiner, Art Unit 1651
/MELENIE L GORDON/Supervisory Patent Examiner, Art Unit 1651