DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. 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
2. Applicant’s Amendment received 07/24/2025 and Applicant’s election of species received 12/22/2025 are acknowledged.
3. Claims 1-25 are pending. Applicant’s election of the following species: SEQ ID NO: 1 as the sequence of the polypeptide; immunoglobulin as the proteinaceous moiety; and glycosylated on all of N81, N97, and N144 of SEQ ID NO: 1, filed 12/22/2025, is acknowledged.
4. Claims 1-3, 5-6, 8-17, and 22 are withdrawn from consideration under 37 CFR 1.142(b) as being drawn to nonelected invention and species.
5. Claims 4, 7, 18-21, and 23-25 are currently under examination, as they are drawn to a method of treating fibrosis comprising administering a polypeptide comprising a propeptide of lysyl oxidase.
Priority
6. This application is a CON of PCT/IL2020/05048 filed 04/30/2020, which claims benefit of provisional application no. 62/977,792 filed 02/18/2020. Therefore, the effective filing date of the instant invention is 02/18/2020.
7. The following new ground of rejections are necessitated by the amendment submitted 07/24/2025.
Previous Rejections
Claim Rejections - 35 USC § 103
8. 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.
9. Claims 4 and 7 stand rejected under 35 U.S.C. 103 as being unpatentable over TRACKMAN et al., (US 20080261870 A1; listed on the IDS filed 01/10/2022) in view of LIDNER (US /20050147602 A1; published 04/07/2005) for the same reasons set forth in the previous Office action, mailed 4/25/2025.
Response to Arguments
10. Applicant's arguments filed 07/24/2025 have been fully considered but they are not persuasive. In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, the combination of Trackman et al. (US 20080261870 A1, IDS Reference, “Trackman”) in view of Lidner (US 20050147602 A1, “Lidner”) is sufficient to establish a prima facie case of obviousness of the instant invention. It is not necessary for Trackman to teach a propeptide that does not have lysyl oxidase enzymatic activity (LOX-PP) as a direct inhibitor of LOX enzymatic activity. While Trackman does teach inhibition of LOX catalytic activity using BAPN does not affect the transformed phenotype, it is important to remember this is in the context of oncogenic transformation. The instant invention is clearly claimed to not be associated with cancer or bone disease (instant claim 4). As noted in the previous rejection, Trackman teaches methods of treatment with a therapeutic composition comprising an active portion of the lysyl oxidase propeptide, wherein said active agent does not have lysyl oxidase enzymatic activity (LOX-PP). Furthermore, Lidner does teach relevance of LOX specifically to cross-linking of collagen fibrils (see, e.g., paragraphs [0031] and [0085]), and therefore, by extension, to fibrosis. A person of skill would find the concept of inhibiting lysyl oxidase enzymatic activity from Lidner’s inhibition of BMP1 showing inhibition of collagen deposition (paragraph [0085]). A person of skill in the art would be motivated to use a LOX-PP as taught by Trackman, to prevent cross-linking of collagen fibrils and therefore, fibrosis, as taught by Lidner. The previous 103 rejection is maintained.
Double Patenting
11. 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 www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
12. Claim 4 stands provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 18/804,150 in view of Pugliese et al. (Antibiotics. 2021 May 28; 10(6):648. PMID: 34071639).
13. Applicant's arguments filed 07/24/2025 have been fully considered but they are not persuasive. Applicant respectfully requests deferring addressing issues of Double Patenting until indication of allowable subject matter. Regarding Double Patenting – the rejection is maintained until allowable subject matter is found or identified.
New Rejections
Claim Rejections - 35 USC § 112
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.
14. Claims 18-19 are 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.
The scope of claim 18 encompasses a broad genus of proteinaceous modifications which confer enhanced stability as compared to a native form of LOX.
Claim 19 is included because it is dependent on claim 18.
Claim 18, given broadest reasonable interpretation consistent with the specification, reads on a genus of conjugated LOX propeptides with proteinaceous moieties. This broadest claim (claim 18) does not indicate any specific structure for the proteinaceous moieties nor does it indicate any specific location on the LOX-PP propeptide where binding would occur.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the written description inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116.). Consequently, Applicant was not in possession of the instant claimed invention. See University of California v. Eli Lilly and Co. 43 USPQ2d 1398.
Applicant is invited to point to clear support or specific examples of the claimed invention in the specification as-filed.
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.
15. Claims 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over Trackman et al. (US 20080261870 A1, IDS Reference, “Trackman”) in view of Lidner (US 20050147602 A1, “Lidner”) as applied to claims 4 and 7 above, and further in view of Czajkowsky et al. (EMBO Mol Med. 2012; 4(10): 1015-1028, “Czajkowsky”).
The teachings of Trackman have been discussed previously, supra.
The teachings of Lidner have been discussed previously, supra.
Neither Trackman nor Lidner teach a chimeric polypeptide comprising a propeptide of LOX and a proteinaceous modification which imparts said polypeptide with enhanced stability under physiological conditions as compared to a native form of said polypeptide (claim 18), nor do they teach said proteinaceous modification being immunoglobulin (claim 19), nor do they teach said immunoglobulin comprises an Fc domain (claim 20).
However, in analogous art, Czajkowsky teaches Fc-based fusion proteins composed of an immunoglobulin Fc domain that is directly linked to another peptide (see introduction and figure 1A). Czajkowsky further teaches that from a biophysical perspective, the Fc domain folds independently and can improve the solubility and stability of the partner molecule both in vitro and in vivo.
It would have been obvious to one of ordinary skill in the art at the time the invention was made to combine the LOX-PP of Trackman with an Immunoglobulin Fc domain as taught by Czajkowsky to enhance the stability of the polypeptide for use against fibrosis as taught by Lidner.
One of ordinary skill in the art at the time the invention was made would have been motivated to do so because increased stability of an Fc fusion can increase plasma half-life, which in turn can improve therapeutic efficacy (see p. 1018 last paragraph and 1019 first paragraph).
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
16. Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over Trackman et al. (US 20080261870 A1, IDS Reference, “Trackman”) in view of Lidner (US 20050147602 A1, “Lidner”) as applied to claims 4 and 7 above, and further in view of Vora et al. (Biochemistry., 2010; 49(13): 2962-2972, “Vora”).
The teachings of Trackman have been discussed previously, supra.
The teachings of Lidner have been discussed previously, supra.
Neither Trackman nor Lidner teach glycosylation on all of N81, N97, and N144 of instant SEQ ID NO: 1.
However, in analogous art, Vora teaches that LOX-PP is unusual in that it is a highly basic protein with the potential for post-translational modifications that could account for its slow mobility on SDS PAGE. N-linked glycosylation of Pro-LOX in the LOX-PP region is known, but O-linked glycosylation of LOX has not been previously investigated. As noted, several studies have now demonstrated important biological activities of recombinant LOX-PP (rLOX-PP) expressed and purified from transfected T-Rex-293 cells. The present study was initiated with the goal of characterizing structural aspects of rLOX-PP with an ultimate aim to gain new insights into possible structure/function relationships of LOX-PP.
It would have been obvious to one of ordinary skill in the art at the time the invention was made to express the LOX-PP as taught by Trackman using an HEK expression system as taught by Vora, for use against collagen deposit as taught by Lidner.
One of ordinary skill in the art at the time the invention was made would have been motivated to do so because glycosylated LOX-PP is biologically active and thermally stable. Although Vora et al. is silent with regard to the LOX-PP being site-specifically glycosylated at N81, N97, and N144 of SEQ ID NO: 1, it is noted that a compound and all of its properties are inseparable; they are one and the same thing (see In re Papesch, CCPA 137 USPQ 43; In re Swinehart and Sfiligoj, 169) USPQ 226 (CCPA 1971)). Therefore, in the absence of evidence to the contrary, the LOX-PP composition expressed by Vora et al. would inherently be fully glycosylated at these sites. Thus, the Vora et al. reference meets all the limitations of claim 21.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
17. Claims 23-25 are rejected under 35 U.S.C. 103 as being unpatentable over Trackman et al. (US 20080261870 A1, IDS Reference, “Trackman”) in view of Lidner (US 20050147602 A1, “Lidner”) as applied to claims 4 and 7 above, and further in view of Martins et al (DNA Seq., 2001; 12: 215-227, “Martins”).
The teachings of Trackman have been discussed previously, supra. Trackman further teaches a human propeptide of LOX (LOX-PP) of SEQ ID NO: 1 which is 98.2% identical to the instant SEQ ID NO: 1 (1 AA mismatch, see alignment below)
Qy 1 APPAAGQQQPPREPPAAPGAWRQQIQWENNGQVFSLLSLGSQYQPQRRRDPGAAVPGAAN 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 APPAAGQQQPPREPPAAPGAWRQQIQWENNGQVFSLLSLGSQYQPQRRRDPGAAVPGAAN 60
Qy 61 ASAQQPRTPILLIRDNRTAAARTRTAGSSGVTAGRPRPTARHWFQAGYSTSRAREPGASR 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||
Db 61 ASAQQPRTPILLIRDNRTAAARTRTAGSSGVTAGRPRPTARHWFQAGYSTSRAREAGASR 120
Qy 121 AENQTAPGEVPALSNLRPPSRVDGMVG 147
|||||||||||||||||||||||||||
Db 121 AENQTAPGEVPALSNLRPPSRVDGMVG 147
The teachings of Lidner have been discussed previously, supra.
Neither Trackman nor Lidner teach a 100% match to the instant SEQ ID NO: 1 of human LOX-PP.
However, in analogous art, Martins teaches a 100% match to the instant SEQ ID NO: 1 of human LOX-PP (see alignment below).
Qy 1 APPAAGQQQPPREPPAAPGAWRQQIQWENNGQVFSLLSLGSQYQPQRRRDPGAAVPGAAN 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 22 APPAAGQQQPPREPPAAPGAWRQQIQWENNGQVFSLLSLGSQYQPQRRRDPGAAVPGAAN 81
Qy 61 ASAQQPRTPILLIRDNRTAAARTRTAGSSGVTAGRPRPTARHWFQAGYSTSRAREPGASR 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 82 ASAQQPRTPILLIRDNRTAAARTRTAGSSGVTAGRPRPTARHWFQAGYSTSRAREPGASR 141
Qy 121 AENQTAPGEVPALSNLRPPSRVDGMVGD 148
||||||||||||||||||||||||||||
Db 142 AENQTAPGEVPALSNLRPPSRVDGMVGD 169
It would have been obvious to one of ordinary skill in the art at the time the invention was made to substitute one amino acid for another to produce the polypeptide of instant SEQ ID NO: 1. This would be simple substitution – swapping similar features that serve the same purpose.
Claim 23 is included in this rejection because those characteristics (EC50 of 100-500nM, as determined by ELISA assay; KD of 10-100 nM, as determined by a microscale thermophoresis; transition midpoint of 20-70 degrees Celsius, as determined by differential scanning fluorimetry (DSF); and/or capable of reducing at least one of fibrillar collagen and cross-linked collagen, as determined by SHG microscopy) would be inherent since both the reference and instant polypeptides are identical. "Structural similarity, alone, may be sufficient to give rise to an expectation that compounds similar in structure will have similar properties." In re Merck & Co., Inc., 231 USPQ 375,379.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
18. No claims are allowed.
19. 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.
20. Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALAN ALFANO whose telephone number is (571)272-3092. The examiner can normally be reached M-F 8-5 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached at 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ALAN ALFANO/Examiner, Art Unit 1641
/MAHER M HADDAD/Primary Examiner, Art Unit 1641
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