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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 05/13/2026 has been entered.
Status of Claims
Claims 1, 3, 13, 17, 30-34 and 38-39 are pending following the Reply filed 05/13/2026. Claim 6 has been cancelled. Claims 1 and 17 have been amended without adding new matter. Claims 30-31, 33-34 and 38-39 are withdrawn. Claims 1, 3, 13, 17 and 32 have been examined on the merits.
Information Disclosure Statement
The information disclosure statement (IDS) filed on 05/13/2026 has been considered by the examiner.
Withdrawn
The objections to claims 1 and 17 have been withdrawn in light of the amendments.
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, 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., they are 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 9 and 10.
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 a therapeutic polypeptide (anti-cancer agent) 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 serine protease having cancer specific killing capability is porcine pancreatic elastase (PPE/pELA1) (see pg. 8, para. [0020]). Becker teaches the porcine pancreatic elastase (pELA1) or variant thereof has an amino acid sequence represented by SEQ ID NO: 6 (see pg. 14, para. [0025]). The following sequence alignment compares Becker’s SEQ ID NO: 6 (bottom) to the “heterologous protease cleavage site” of instant SEQ ID NO: 9 (top):
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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), Xaa2 is alanine (A), Xaa3 is alanine (A), Xaa4 is glycine (G), Xaa5 is valine (V), Xaa6 is valine (V), 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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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 porcine pancreatic elastase (PPE) 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 porcine pancreatic elastase 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, it would have been obvious for the proprotein to have retained the heterologous cleavage site for the reasons discussed above. Becker teaches the porcine pancreatic elastase (PPE) or variant thereof has an amino acid sequence represented by SEQ ID NO: 6, as discussed above. As shown in the following alignment, instant SEQ ID NO: 1 (top) is identical to Becker’s SEQ ID NO: 6 (bottom):
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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 31-266 of instant SEQ ID NO: 1 (top) are identical to the same region of Becker’s SEQ ID NO: 6 (bottom):
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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 Franano does not provide a sufficient technical basis to arrive at the claimed cleavage sites of SEQ: 9 or 10 with a reasonable expectation of successful cleavage activity. Applicant argues that a person would have been cautioned against any expectation of successful activity by reviewing the empirical results from Tables 4 & 5 of Franano. Franano tested 22 total cleavage sites and of the 16 constructs that showed at least intermediate to high shaker flask yield, at least five (5) showed no cleavage activity, as indicated by “No Conversion Detected.”
Applicant’s arguments have been fully considered but they are not persuasive.
Applicant is reminded that one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, Applicant’s arguments do no not appear to make any mention regarding the teachings of the Becker reference.
While it is noted in the rejection that all of the cleavage domains in Table 4 of Franano have a glycine (G) at position 8 (P3’), Becker’s SEQ ID NO: 6 already has a glycine (G) at this position. Hence, a person of skill would not have been required to modify this feature to arrive at the claimed invention. Furthermore, the majority of Franano’s “constructs” did show cleavage activity, as acknowledged in Applicant’s argument of there being only five that did not show this activity.
Applicant further argues that none of the “empirically-tested” cleavage sites in Franano have Val at P1 as do SEQ ID NOs: 9 and 10, a position that Franano teaches is important for being part of both the recognition sequence (P3-P1) and the cleavage bond (P-P1’).
Applicant’s arguments have been fully considered but they are not persuasive, because Becker’s SEQ ID NO: 6 already has a Val at the P1 position. Hence, a person of skill would not have been required to modify this feature to have arrived at the claimed invention.
Furthermore, Franano teaches that the amino acid residue at position Xaa5 (“P1”) may be a valine (Val), as discussed in the rejection. Applicant is reminded that “[t]he use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain." In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)). Moreover, disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). See MPEP 2123. In the instant case, the fact that a cleavage domain variant having a Val at the P1 position was not “empirically tested” by Franano does not constitute a “teaching away” from Franano’s broader disclosure.
Applicant further argues that none of the “empirically tested” cleavage sites in Franano have a Gly at P2, as do SEQ ID NOs: 9 and 10, a position that Franano teaches is important for being part of the recognition sequence (P3-P1).
Applicant’s arguments have been fully considered but they are not persuasive.
Franano teaches that the amino acid residue at position Xaa4 (“P2”) may be a glycine (Gly), as discussed in the rejection. Applicant is reminded that “[t]he use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain." In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)). Moreover, disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). See MPEP 2123. In the instant case, the fact that a cleavage domain variant having a Gly at this position was not “empirically tested” by Franano does not constitute a “teaching away” from Franano’s broader disclosure.
See also MPEP 2121(I) which states “When the reference relied on expressly anticipates or makes obvious all of the elements of the claimed invention, the reference is presumed to be operable. Once such a reference is found, the burden is on applicant to rebut the presumption of operability. In re Sasse, 629 F.2d 675, 207 USPQ 107 (CCPA 1980).”
Therefore, in the absence of any evidence to the contrary, Franano’s teaching of a Gly at position P2 is presumed to be an operable embodiment of the disclosure.
Applicant further argues that only two of the “empirically tested” cleavage sites (SEQ ID NOs: 40 and 46) in Franano have an Ala at P3 of the recognition sequence (P3-P1), as do SEQ ID NOs: 9 and 10, and neither of these cleavage sites showed any evidence of cleavage activity.
Applicant’s arguments have been fully considered but they are not persuasive, because Becker’s SEQ ID NO: 6 already has an Ala at the P3 position. Hence, a person of skill would not have been required to modify this feature to have arrived at the claimed invention.
Furthermore, Franano teaches that the amino acid residue at position Xaa3 (“P3”) may be an alanine (Ala), as discussed in the rejection.
It should also be noted that the conversion rate of Franano’s SEQ ID NO: 40 is listed as “Not Applicable” (see Table 5). Hence, it does not appear Franano was able to test the cleavage activity of SEQ ID NO: 40. It should also be noted that Franano’s SEQ ID NO: 46 comprised a glycine (G) at Xaa5 (P1) which is important as being both part of the recognition site and the cleavage bond of the domain, as acknowledged by Applicant above. However, in the portion of Franano’s disclosure relied upon in the rejection, Franano specifically teaches against having a glycine residue at Xaa3 (see pg. 15, para. [0141]) or Xaa5 (see pg. 16, para. [0143]). In fact, SEQ ID NOs 44-47 and 62, which Applicant acknowledges to have showed no cleavage activity, all had a glycine at the P1 and/or P3 positions. Therefore, a person of skill would have just as easily concluded that it was the presence of glycine at P1 and/or P3 that resulted in the lack of activity, which is consistent with Franano expressly teaching away from such embodiments.
Nevertheless, MPEP 2121(I) states “When the reference relied on expressly anticipates or makes obvious all of the elements of the claimed invention, the reference is presumed to be operable. Once such a reference is found, the burden is on applicant to rebut the presumption of operability. In re Sasse, 629 F.2d 675, 207 USPQ 107 (CCPA 1980).” In the instant case, Becker and Franano both teach an alanine (Ala) at the P3 position, and, in the absence of any evidence to the contrary, Franano’s teaching of an Ala at position P3 is presumed to be an operable embodiment of the disclosure.
Applicant concludes that SEQ ID NOs: 9 and 10 show multiple differences relative to the empirically cleavage sites in Franano, in each of P1, P2, and P3, which Franano identifies as being important for recognition and cleavage activity but provides no empirical basis to expect Applicant’s claimed residues at these positions to work. If anything Franano teaches away from an Ala residue at P3, as can be found in SEQ ID NOs: 9 and 10. Given the multiple layers of foregoing uncertainties, which go against any reasonable expectation of success in designing an active cleavage site according to SEQ ID NOs: 9 and 10, Applicant respectfully submits that a prima facie case of obviousness has not been established.
Applicant’s arguments have been fully considered but they are not persuasive for at least the reasons discussed above:
(1) Becker discloses SEQ ID NO: 6 which comprises a cleavage site comprising an Ala at P3 and a Val at P1, while Franano expressly teaches that the cleavage site may have an Ala at P3 and a Val at P1.
(2) Franano expressly teaches that the amino acid residue at position Xaa4 (“P2”) may be a glycine (Gly), while expressly teaching the amino acid residues at positions Xaa3 (“P3”) and Xaa5 (“P1”) may not be glycine (Gly).
(3) The examiner submits that there can be no conclusion that Franano “teaches away” from an Ala residue at P3, because the presence of this residue at this specific position is expressly taught in Franano’s embodiments. Furthermore, Franano’s embodiments expressly teach away from other features (i.e., glycine at P1 and/or P3) that were shared by the variants lacking cleavage activity. Moreover, Franano makes no statement attributing this lack of activity to the presence of Ala at P3.
(4) Applicant has not provided any further evidence to rebut the presumption of operability of the prior art relied upon in the rejection.
Conclusion
No claims are allowed.
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/DENNIS IGNATIUS ARMATO JR/Examiner, Art Unit 1651
/MELENIE L GORDON/Supervisory Patent Examiner, Art Unit 1651
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