DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 9/24/2025 has been entered.
Applicant's arguments filed 9/24/2025 have been fully considered but they are not persuasive
Claims 2-11, 19, 23-24, and 29 have been cancelled. Claim 32 has been newly added.
Election/Restrictions
Applicant’s election of Group I in the reply filed on 5/13/2024 is again acknowledged.
Claims 26-28 and 30-31 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 5/13/2024.
Specification
The replacement sequence listing submitted 9/24/2025 and the amendments to the specification are acknowledged.
Drawings
The replacement drawing for Figure 1 received on 9/24/2025 is acceptable.
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.
Claims 1, 12-18, 20-22, and 25 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.
Independent claim 1 has been amended to remove the limitation that the IGF-II mutein is “at least 70% identical to mature human IGF-II (SEQ ID NO: 1).” The claims are no longer required to retain any particular sequence identity to SEQ ID NO: 1. No basis was pointed to and none is apparent. The specification and original claims all contain this limitation. Claim 1 is not limited to only the recited deletion and substitution in claim 1 in view of the “comprising” language. See also mutations permitted by at least dependent claims 12-17.
The claims constitute new matter.
Double Patenting
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.
Claims 1, 15-16, 18, 20-22, 25, and 32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 23-24 and 35-41 of copending Application No. 17/829,620 (9/24/2025 claim set). Although the claims at issue are not identical, they are not patentably distinct from each other.
The instant application and the co-pending application are related applications and have the same effective filing date through common parent application 15/657,764 (now U.S. Patent No. 11,351,231). One is not junior or senior to the other. The instant application is a CON of 16/869,862 (now abandoned) which is a CON of 15/657,764. Application 17/829,620 is a CON of 15/657,764. Double patenting is not prohibited as these applications are not divisional applications.
Copending claims 23, 35-38, and 41 are directed to nucleic acids encoding fusion proteins having the limitations of the instant claims. Copending claims 24 and 40 are directed to a cell containing the nucleic acid of claim 23 and copending claim 39 is directed to a recombinant method of making fusion proteins. Copending claims 23-24 and 41 map to instant claims 1, 15-16, and 25. Note that co-pending claims 40-41 (particularly claim 41) include the amino acids of SEQ ID NO: 1 recited in instant claims 15-16. Co-pending claim 35 maps to instant claim 18. Copending claims 36-38 map to instant claims 20-22, respectively. It would have been obvious to recombinantly produce the fusion proteins as in copending claim 39 by using the nucleic acids of the co-pending claims to arrive at the fusion proteins of the instant claims. It would have been obvious to formulate the recombinantly produced fusion protein with a pharmaceutically acceptable carrier as in instant claim 25.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Applicant has acknowledged this double patenting rejection. No argument has been made. No properly executed terminal disclaimer has been submitted.
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(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 1, 12-18, 20-22, 25, and 32 are rejected under 35 U.S.C. 103(a) as being unpatentable over LeBowitz et al. (U.S. Patent Application Publication 2005/0244400, of record) in view of Lebowitz et al. (U.S. Patent No. 7,396,811, of record), Glass et al. (U.S. Patent Application Publication 2006/0166328, of record), Edwards et al. (U.S. Patent No. 5,736,363, of record) and Molloy et al. (of record).
LeBowitz et al. (PGPUB 2005/0244400) discloses a fusion protein of IGF-II and human acid alpha-glucosidase (GAA). The fusion protein includes a spacer such as Gly-Ala-Pro between IGF-II and GAA. (See instant claims 21-22.) The GAA can include amino acids 70-952 of human GAA. (See instant claim 20.) Mutations to the IGF-II include deletion or replacement of amino acids 29-40. IGF-II mutations disclosed include retention of at least amino acids 48-55 that binds the cation-independent mannose-6-phosphate receptor. (See instant claims 1 and 15-17.) Substitution of IGF-II residues Tyr 27 with Leu is disclosed and diminished the affinity of IGF-II for the IGF-I receptor. (See instant claims 13-14 and 18.) Deletion of residues 1-7 of human IGF-II is disclosed and resulted in a 30-fold decrease in affinity for the human IGF-I receptor. The amino terminal amino acids 1-7 and/or the carboxy terminal residues 62-67 of IGF-II can be deleted or replaced. (See instant claims 1 and 10-12.) Additionally, amino acids 29-40 can be deleted or replaced without altering the folding of the remainder of the polypeptide or binding to the cation-independent M6P receptor. Pharmaceutical compositions are disclosed. See at least abstract, claims, examples, and paragraphs [0007, 0010, 0012, 0058-0079, 0082, and 0098-0115].
LeBowitz et al. (PGPUB 2005/0244400) does not suggest the specific substitution of Ala for Arg at amino acid position 37 of SEQ ID NO: 1 (IGF-2) as recited in instant claim 1. LeBowitz et al. (PGPUB 2005/0244400) does not disclose mutations that cause diminished binding affinity for the insulin receptor relative to the affinity of naturally-occurring human IGF-II for the insulin receptor as recited in instant claim 1.
Lebowitz et al. (U.S. Patent No. 7,396,811) discloses and claims a therapeutic fusion protein comprising a lysosomal enzyme and a mutein of mature human IGF-II that binds human
cation-independent mannose-6-phosphate receptor in a mannose-6-phosphate independent manner, wherein the mutein differs from mature human IGF-II (A) only by a deletion or a replacement of amino acids 29-40 or (B) only by a deletion or a replacement of amino acids 1-7, wherein the mutein of mature human IGF-II is fused N-terminally to the lysosomal enzyme and wherein the therapeutic fusion protein is produced in a mammalian expression system using an IGF-II signal peptide and is therapeutically active in vivo. See at least claims 2 and 4. This indicates that human IGF-II with deletion of amino acids 1-7 and replacement (i.e. substitution) of any amino acids in the 29-40 range will still bind cation-independent mannose-6-phosphate receptor in a mannose-6-phosphate independent manner. That is, amino acid 37 of IGF-II is not required for binding to the cation-independent mannose-6-phosphate receptor in a mannose-6-phosphate independent manner. In addition, claim 3 discloses the same binding where amino acids 62-67 of IGF-II are replaced or deleted as in instant claim 12. In addition, claim 10 discloses the same binding where amino acid Tyr27 is substituted in IGF-II in combination with the deletion or replacement of amino acids 1-7 as in instant claims 13-14.
Glass et al. discloses fusion proteins of IGF-II. Glass et al. specifically suggests substituting Arg37 and/or Arg38 with another amino acid. Glass et al. specifically suggests substituting with alanine (Ala) and specifically discloses the substitution Arg37Ala. These substitutions prevent cleavage. See at least paragraph [0009, 0034-0035].
Edwards et al. discloses and claims substituting arginine at amino acids 37 and/or 38 in IGF-II with different amino acids to make the IGF-II resistant to cleavage by proteases. The amino acid substituted can be a non-basic or neutral amino acid such as Ala. These substitutions result in lower affinity of IGF-II for the insulin receptor and retain binding to the IGF-II receptor. See at least abstract; column 3, lines 8-47; column 4; and claims.
Molloy et al. discloses that human furin is a predominantly Golgi membrane-localized endoprotease that can efficiently process precursor proteins at paired basic residues such as Arg-Arg. See abstract.
LeBowitz et al. (PGPUB 2005/0244400) discloses that the sequence of IGF-II can include a variety of mutations and suggests substituting in the range of amino acids 29-40. The intended use of the fusion proteins of LeBowitz et al. (PGPUB 2005/0244400) is to target a therapeutic agent to a lysosome using a protein, or an analog of a protein, that specifically binds a cellular receptor for that protein. The exterior of the cell surface is topologically equivalent to endosomal, lysosomal, golgi, and endoplasmic reticulum compartments. Thus, one of ordinary skill in the art would have been motivated to produce IGF-II and human acid alpha-glucosidase (GAA) fusion proteins that were resistant to cleavage by endoproteases such as furin which are located in the Golgi membrane, for example.
It would have been obvious to delete amino acids 1-7 of the mature human IGF-II sequence of SEQ ID NO: 8 (equivalent to instant SEQ ID NO: 1) as disclosed in Leibowitz et al. (U.S. Patent No. 7,396,811) and then substitute alanine for arginine at amino acid position 37 in this sequence as suggested by Glass et al. and Edwards et al. in order to block protease cleavage in IGF-II. One would have been motivated to do so in order to prevent cleavage at the dibasic (RR) site in IGF-II as taught by Edwards et al. and was known to be a furin cleavage site as taught by Molloy et al. At least LeBowitz et al. (PGPUB 2005/0244400) discloses that deletion of amino acids 1-7 of IGF-II provides the activity recited in instant claim 18. Both LeBowitz et al. references disclose that IGF-II having replacement (i.e. substitution) of any amino acids in the 29-40 range would still bind cation-independent mannose-6-phosphate receptor in a mannose-6-phosphate independent manner as recited in instant claim 1. Edwards et al. discloses that an Arg37Ala substitution in IGF-II results in lower affinity of IGF-II for the insulin receptor and retains binding to the IGF-II receptor as recited in instant claim 1. This mutation also disrupts the furin cleavage site in IGF-II. With respect to dependent claims 12-14, these mutations would still bind cation-independent mannose-6-phosphate receptor in a mannose-6-phosphate independent manner as recited in instant claim 1 as taught by LeBowitz et al. (U.S. Patent No. 7,396,811). With respect to dependent claims 15-17, these claims include embodiments where the IGF-II mutein retains the wild-type sequence at amino acid positions 8-55 and would still bind cation-independent mannose-6-phosphate receptor in a mannose-6-phosphate independent manner as recited in claim 1. Note that the naturally occurring amino acids in IGF-II at amino acid positions 54 and 55 would be Ala and Leu, respectively. These would be uncharged or negatively charged at pH 7.4. (This is supported by paragraphs [12-13, and 81] and claim 17 of WO 03/102583, of record.)
It would have been obvious to make the claimed fusion protein of IGF-II and human acid alpha-glucosidase (GAA) suggested by the combination of the prior art references as discussed above .
Applicant’s arguments are unpersuasive. All of the elements of the claims are taught or suggested by the prior art. The prior art provides motivation to combine all of the elements of the claims. A person of ordinary skill would have been motivated to make the claimed fusion proteins. In response to applicant’s arguments on page 9, last paragraph, of the 9/24/2025 response about “amino acids 29-40 can likely be eliminated” (italic emphasis by applicant), the claims of Lebowitz et al. (U.S. Patent No. 7,396,811) recite retention of the binding to the human cation-independent mannose-6-phosphate receptor in a mannose-6-phosphate-independent manner for the IGF-II muteins. Patent claims are presumed to be valid. It would have been within the skill of those in the art to make the fusion protein suggested by the prior art as evidenced by at least both LeBowitz et al. publications. One would have expected to produce a fusion protein having all of the recited functional activities for the reasons set forth above. Each of the recited activities were known in the art with respect to mutated forms of IGF-II and the activities were independent of each other.
Again, Edwards et al. discloses that substituting Arg37 will result in diminished binding affinity for the insulin receptor. Edwards et al. also discloses that binding to the IGF-II receptor is retained for the mutation Arg37Ala.
Again, LeBowitz et al. (PGPUB 2005/0244400) discloses that deleting amino acids 1-7 will result in diminished binding affinity for the IGF-1 receptor.
Applicant’s arguments with respect to Glass et al. suggesting other modifications does not diminish or teach away from the specific suggestion to substitute alanine for arginine at amino acid position 37. This substitution can be made as an independent mutation and does not need to be made in combination with any other mutations disclosed by Glass et al. See at least part (iii) of paragraph [0034]. One of ordinary skill in the art would have been motivated to make this Arg37Ala mutation in view of this specific suggestion in combination with the disclosures of Edward et al. and Molloy et al. regarding reducing protease cleavage such as by furin. Note that only claim 32 excludes inclusion of the mutations at amino acid position 38 of SEQ ID NO: 1. That is, the claims are not limited to the Arg37Ala mutation within amino acids 30-40 of SEQ ID NO: 1. The recitation of “comprises” in claim 1 permits other changes.
Applicant’s arguments with respect to Edwards et al. are not persuasive. The prior art can suggest making the claimed mutations for reasons that differ from applicant. This does not render the claims unobvious. Proteases that cleaved at dibasic cleavage sites (such as Arg-Arg) would have been known to exist in both bacterial and mammalian cells. Furthermore, the fusion protein encoded by the claimed nucleic acid could have been produced in bacterial cells as well as mammalian cells. See for example, paragraph [0020] of Glass et al. That is, there are multiple reasons that one of ordinary skill in the art would have wanted to substitute Arg37 in IGF-II to remove a dibasic cleavage site.
Applicant’s arguments with respect to Glass not disclosing the effect of an IGF-II mutein having an amino acid substitution at Arg37 on cation-independent mannose-6-phosphate receptor binding affinity are not persuasive. Lebowitz et al. discloses that amino acids 29-40 (i.e. including Arg37) can be eliminated or replaced without altering the binding to the cation- independent M6P receptor. One of ordinary skill in the art would have understood from the teachings of Lebowitz et al. that this portion of IGF-II was not critical for this particular activity.
One of ordinary skill in the art would have been motivated and able to construct the fusion protein with an expectation of success. At least Lebowitz et al. and Glass et al. demonstrate the level of skill in manipulating and mutating protein sequences to obtain proteins with desired properties. It would have been routine to eliminate protease cleavage sites as evidenced by the prior art to at least Glass et al. and Edwards et al. and Lebowitz et al. discusses the modifications that would have provided the remaining properties. There would have been an expectation of success at producing the fusion protein possessing the recited properties. The combination of the prior art suggests making the claimed embodiment. The prior art was well aware of cleavage sites in recombinant proteins and how to mutate them to avoid cleavage.
Applicant has not established any unexpected results for the fusion protein in the claims. The resistance to furin cleavage, diminished binding affinity for the insulin receptor, and the retained binding for the human CI-M6PR (instant claim 1) as well as diminished binding affinity for the human IGF-I receptor (instant claim 18) limitations have all been addressed. Contrary to applicant’s arguments, the claims do not require any more particular levels of furin resistance or binding affinity to the various receptors. The obviousness rejection addresses each of the properties recited in the claims with respect to the teachings of the prior art. The claimed fusion proteins would have been obvious.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARIANNE P ALLEN whose telephone number is (571)272-0712. The examiner can normally be reached 7:00-3:30 EST Monday-Friday.
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/Marianne P Allen/Primary Examiner, Art Unit 1647
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