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 the Application
1. Claims 1-4, 6-9, 11-15, 17, 19, 22, 27-28, and 31 are pending and subject to examination on the merits. Claims 27-28 are withdrawn from consideration as being drawn to non-elected subject matter. Claims 1-4, 6-9, 11-15, 17, 22, and 31 are currently under examination.
Priority
2. Acknowledgement is made of applicant’s claim for foreign priority based on an application filed in EP (PCTEP2021056947) on 18 March 2021. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Withdrawn Objections/Rejections
3. The objection to the specification for an embedded hyperlink is withdrawn, since the hyperlink was removed.
4. The objection to the Drawings for the missing x-axis label is withdrawn, since the Drawings were amended to include an x-axis label.
5. The objection to claim 12 for being dependent on a rejected claim (claim 1) is withdrawn, since the claim was rewritten to be independent.
6. The objection to claim 14 for being dependent on a rejected claim (claim 1) is withdrawn, since the claim was rewritten to be independent.
Maintained/Modified Rejections—necessitated by claim amendments
Claim Rejections - 35 USC § 102
7. 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.
8. 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.
9. Claims 1-4, 6-9, 11, 13, 15, 17, 19, 22, and 31 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Schmitt et al (Schmitt et al., 2014, EP 2 792 686 A1—cited on the IDS filed 28 November 2023) as evidenced by BLAST Sequence Alignment (“Schmitt Alignment 1”, 2014, downloaded from <https://blast.ncbi.nlm.nih.gov/Blast.cgi> on 04 March 2026, provided as a PDF herein), ABSS Sequence Alignment (“Schmitt Alignment 2,” 2014, downloaded from <https://abss.uspto.gov/abss4examiners/> on 04 March 2026, provided as a PDF herein), BLAST Sequence Alignment (“Schmitt Alignment 3,” 2014, downloaded from <https://blast.ncbi.nlm.nih.gov/Blast.cgi> on 04 March 2026, provided as a PDF herein), BLAST Graphic summary (“Schmitt Graphic Summary SEQ ID NO: 36,” 2014, downloaded from <https://blast.ncbi.nlm.nih.gov/Blast.cgi> on 04 March 2026, provided as a PDF herein), ABSS Sequence Alignment (“Schmitt Alignment 4,” 2014, downloaded from <https://abss.uspto.gov/abss4examiners/> on 26 February 2026, provided as a PDF herein), and Expasy (“Expasy Peptide Cutter,” 2005, downloaded from < https://web.expasy.org/cgi-bin/peptide_cutter/peptidecutter.pl#top> on 04 March 2026, provided as a PDF herein). Regarding claims 1-2, 6-8a, 22, and 31, drawn to an isolated polypeptide (or a nucleic acid) comprising a first and second amino acid, where (a) the first amino acid sequence is (a1) 30-200 amino acids in length, (a2) comprising at least two (claim 2) GG repeat sequences, with the general structure of GG1-Linker-GGR2-Linker-GGR3 (Claim 3), of the general GGxGxDxUx (SEQ ID NO: 372), specifically a GGR1: GGKGNDKLY, GGR2: GGEGDDLLK, and GGR3: GGYGNDIYRY (claims 6-8a and 31), (a3) does not comprise a C-terminal secretion signal sequence and the C-terminal sequence TTSA, and (a4) is not SEQ ID NO: 228; and (b) the second amino acid sequence is at least one peptide/polypeptide of interest, and (c) wherein the first and second amino acid sequences are heterologous to each other, and wherein the first amino acid sequence increases the solubility, stability, and/or renaturation efficiency of the second amino acid sequence relative to a polypeptide not comprising the first amino acid sequence. Schmitt et al. teaches nucleic acid sequences comprising hemolysin A gene fragments to improve the expression and production of a peptide or protein of interest (abstract), where the HlyA fragments truncated stepwise with GG repeats from the N-terminus readily formed inclusion bodies and subsequent refolding, where only proteins with said GG repeats readily formed inclusion bodies and were able to be recovered and refolded in appreciable concentrations (paragraphs 0138-0140). Additionally, since the GG repeats are identical between Schmitt et al. and the instant claims, the demonstration of increased solubility, stability, and/or renaturation efficiency of the second amino acid sequence is an inherent property of the GG-repeat sequence, thus anticipating the instant claim. See MPEP 2112.02. Specifically, Schmitt et al. teaches SEQ ID NOs: 35-36 (p. 52-53; SEQ ID NO: 35 is the nucleic acid sequence; SEQ ID NO: 36 is the amino acid sequence--provided below), which is:
MGNSLAKNVLFGGKGNDKLYGSEGADLLDGGEGDDLLK-GGYGNDIYRYLSGYGHHIIDDDGGKEDKLIDGRSTKDFNLDLVSVSKKDSGASPRITSISLCTPGCKTGALMGCNMKTATCHCSIHVK
The above polypeptide (SEQ ID NO: 36) demonstrates a first, second, and third GG repeat sequence (underlined), where the first and second GG repeat units are linked together (“Linker”) by 9 amino acids, and the second and third GG repeat units are linked by a peptide bond (the “-“ above), where the first GG repeat unit is 100% identical to SEQ ID NO: 1 of the instant application, the second GG repeat unit is 100% identical to SEQ ID NO: 2 of the instant application, and the third GG repeat sequence is 100% identical to SEQ ID NO: 3 of the instant application. The first sequence is 71 amino acids in length and shares 100% sequence identity to an RTX toxin hemolysin A fragment from E. coli as evidenced by “Schmitt Alignment 1.” Additionally, there are no secretion sequences and TTSA motifs (See above). SEQ ID NO: 36 is not 100% identical to SEQ ID NO: 228, as evidenced by “Schmitt Alignment 2,” where specifically SEQ ID NO: 36 above has an additional N-terminal Met and an additional 4 amino acids at the C-terminus before the heterologous second amino acid. The second amino acid is a heterologous amino acid sequence from Lactococcus, annotated as MULTISPECIES: gallidermin/nisin family lantibiotic, as evidenced by “Schmitt Alignment 3” and “Schmitt Graphic Summary SEQ ID NO: 36.”
Regarding claim 4, drawn to the general structure being flanked by 1-100 C-terminal amino acids, the above sequence is flanked by 4 amino acids (italicized and underlined above). Regarding claim 9, drawn to the first amino acid sequence with two or more sets of GG repeats of claim 8a-j, the above sequence comprises the combinations disclosed in 8a, SEQ ID NOs: 1-3. Regarding claim 11, drawn to a polypeptide with at least two GG repeats directly linked, the above sequence demonstrates the second two GG repeats directly linked by a peptide bond (denoted by “-“). Regarding claim 13, drawn to the isolated polypeptide of claim 1 being 30-150 amino acids, the above polypeptide is 127 amino acids in length. Regarding claim 15, drawn to the first polypeptide being the first polypeptide of SEQ ID NO: 117, “Schmitt Alignment 4” evidences that the first 66 amino acids of SEQ ID NO: 117 of the instant application (first polypeptide) are 100% identical to amino acids 2-67 of SEQ ID NO: 36 of Schmitt et al. Regarding claim 17, drawn to the second amino acid sequence being 10-1000 amino acids, Schmitt et al. teaches SEQ ID NO: 36 (above), where the second amino acid sequence is 79 amino acids in length. Regarding claim 19, where the first and second amino acid sequences are linked by 4 amino acid, which comprises a protease recognition site for Factor Xa, “Expasy” evidences that the linker at amino acid 71 is a protease recognition and cleavage site for Factor Xa (See p. 2, result 8).
Double Patenting
10. 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.
11. Claims 1-4, 6-9, 11, 13, 15, 17, 19, 22, and 31 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-9, and 12 of copending Application No. 17912066 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘066 claims would necessarily anticipate the instant claims.
The instant claims are drawn to an isolated polypeptide comprising a first and a second amino acid sequence, wherein: (a) the first amino acid sequence is 30 to 150 amino acids in length (claim 13), (a2) comprises at least two (claim 2) GG repeat sequence of the general consensus sequence GGxGxDxUx (SEQ ID NO:372) (and claim 6-9 and 31), wherein each x can independently be any amino acid and U is a hydrophobic, large amino acid selected from the group consisting of F, I, L, M, W, and Y, (a3) does not comprise a C-terminal secretion signal sequence and/or the C-terminal sequence TTSA (SEQ ID NO:21), and (a4) is not SEQ ID NO:228; where each are linked (claims 3 and 11) and flanked with at least 1 C-terminal (claim 4), where said first polypeptide may be SEQ ID NO: 117 (claim 15) and (b) the second amino acid sequence is at least one peptide or polypeptide of interest that is 10-1000 amino acids in length (claim 17) and linked directly or via a linker to the first polypeptide sequence (claim 19, and (c) wherein the first and second amino acid sequence are heterologous to each other (claim 1), and the nucleic acid encoding said polypeptide (claim 22).
The ’066 claims are drawn to a polypeptide variant comprising a first amino acid sequence, wherein the first amino acid sequence comprises:30 to 202 amino acids in length; and at least 80 % sequence identity over its entire length with an amino acid sequence comprised in the amino acid sequence less than 203 continuous amino acids (claim 2) set forth in SEQ ID NO: 1 (HlyA1), wherein the polypeptide variant does not include the full amino acid sequence as set forth in SEQ ID NO: 1 and does not include the C-terminal amino acid motif TTSA (SEQ ID NO:27), wherein the first amino acid sequence comprises any one or more of the amino acid sequence motifs set forth in SEQ ID NO:2 (GNSLA), SEQ ID NO:3 (LKGGYGNDIYRYLSGYGH), SEQID NO:5 (RNWFEKESGDISNHQIEQIFDKSGRIITP), SEQID NO:38 (GGKGNDKLY), SEQ ID NO:39 (GGEGDDLLK), SEQ ID NO:40 (GGYGNDIYR), SEQID NO:41 (GGKGNDKLYSEGADLLDGGEGDDLLK), SEQID NO:42 (GEGDDLLKGGYGNDIYR), and SEQ ID NO:43 (GGKGNDKLYG SEGADLLDGGEGDDLLKGGYGNDIYR). Additionally, the polypeptide of claim 1 additionally comprises a second amino acid sequence that is 10-500 amino acids in length (claims 6 and 9), linked via the C-terminal (claim 7), with a cleavage site (claim 8), and a nucleic acid molecule encoding said polypeptide (claim 12).
The difference between the claims is that the present claims require a heterologous second polypeptide sequence; however, SEQ ID NO: 117 of the instant claims share 100% homology with amino acids 1-157 of SEQ ID NO: 1 of the ‘066 claims. However, the ‘066 claims would still obviate the instant claims, since there is only two alternatives to the addition of a second polypeptide to the first polypeptide, i.e. homologous versus heterologous.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
12. Claims 1-4, 6-9, 11, 13, 15, 17, 19, 22, and 31 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7-10, 18, and 20 of copending Application No. 19107395 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘395 claims would necessarily anticipate the instant claims.
The instant claims are drawn to an isolated polypeptide comprising a first and a second amino acid sequence, wherein: (a) the first amino acid sequence is 30 to 150 amino acids in length (claim 13), (a2) comprises at least two (claim 2) GG repeat sequence of the general consensus sequence GGxGxDxUx (SEQ ID NO:372) (and claim 6-9 and 31), wherein each x can independently be any amino acid and U is a hydrophobic, large amino acid selected from the group consisting of F, I, L, M, W, and Y, (a3) does not comprise a C-terminal secretion signal sequence and/or the C-terminal sequence TTSA (SEQ ID NO:21), and (a4) is not SEQ ID NO:228; where each are linked (claims 3 and 11) and flanked with at least 1 C-terminal (claim 4), where said first polypeptide may be SEQ ID NO: 117 (claim 15) and (b) the second amino acid sequence is at least one peptide or polypeptide of interest that is 10-1000 amino acids in length (claim 17) and linked directly or via a linker to the first polypeptide sequence (claim 19, and (c) wherein the first and second amino acid sequence are heterologous to each other (claim 1), and the nucleic acid encoding said polypeptide (claim 22).
The ’395 claims are drawn to An isolated polypeptide comprising a first and a second amino acid sequence, wherein:(a) the first amino acid sequence (al) comprises in N- to C-terminus orientation the general amino acid sequence element GGR 1-Linker-(GGRN-Linker)~-GGRC (claim 8) wherein GGR1 and each GGRN independently are a first GG repeat sequence of the consensus sequence GGxGxDxUx (claim 7), wherein each x can independently be any amino acid and U is independently a hydrophobic, large amino acid selected from F, V, A, Y, I, L and M; wherein GGRC is a second GG repeat sequence of the consensus sequence GGX11GX12DX13X14X15, wherein X11 is selected from A and D; X12 is selected from N, A, and D; X13 is selected from T and S; X14 is L or F; and X15 is V or I (claim 20); wherein each "Linker" is independently either a peptide bond or an amino acid sequence of 1 to 25 amino acids not comprising the first and/or second GG repeat sequence, wherein n is 0 or an integer from 1 to 10; (a2) wherein the first amino acid sequence is 18 to 300; and (a3) wherein the first amino acid sequence and/or the amino acid sequence element GGR1- Linker-(GGRN-Linker)-GGRC is a non-natural sequence element; here said sequence is derived from SEQ ID NO: 214 (claim 18), (b) the second amino acid sequence is at least one peptide or polypeptide of interest, and (c) wherein the first and second amino acid sequence are heterologous to each other in that they do not occur in combination in a single naturally occurring polypeptide or fragment thereof; wherein, said polypeptide has amino acid sequence derived from SEQ ID NO: 214 (claims 18-19), and the nucleic acid encoding said polypeptide (claim 10).
The difference between the instant claims and those of the ‘395 claim set is the presence of a GGRC in the ‘395 claim set. However, the claims would still anticipate the instant claims, since SEQ ID NO: 117 of the instant claims and SEQ ID NO: 214 of the ‘395 claims share 100% identity, and the instant claims would be able to have a GGRC, since the claims allow for a presence of a C-terminal extension on the first polypeptide.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Allowable Subject Matter
13. Claims 12 and 14 are allowed.
Applicant’s Arguments and Examiner’s Rebuttal
The Applicant argues that the 35 U.S.C. 102(a)(1) and 102(a)(2) over Schmitt et al. should be withdrawn, since claim 1 was amended to recite the first amino acid “(a3) does not comprise a C-terminal secretion signal sequence and the C-terminal sequence TTSA (SEQ ID NO: 25)” and that “the first amino acid sequence increases the solubility, stability, and/or renaturation efficiency of the second amino acid sequence relative to a polypeptide not comprising the first amino acid sequence or relative to the second amino acid sequence not fused to the first amino acid sequence.” The examiner agrees that the a3 was amended from and/or to and; however, this limitation was met with the polypeptide found above, which does not have both a secretion signal and TTSA motif (See above).
Regarding the limitation on “solubility, stability, and/or renaturation efficiency,” the above rejection addresses this claim limitation in that Schmitt et al. teaches increased production and renaturation of the polypeptides with the GG repeat sequences (paragraphs 0138-0140). Additionally, the examiner argues that since these GG repeat sequences share 100% sequence between the instant claims and those taught by Schmitt et al., the increase in solubility, stability, and/or renaturation of the attached polypeptide is an inherent feature of the repeat sequences (See MPEP 2112.02).
Second, the applicant argues that the amendments to claim 1 and 22 differentiate the instant claims from those of the provisional nonstatutory double patenting rejections over applications 17/912,066 and 19/107,395. However, the original claim 1 (which the previous Non-Final office action addressed) had the “a3” limitation, and this limitation was addressed in the previous rejection of record and the current one (found above).
Regarding the limitation on “solubility, stability, and/or renaturation efficiency,” the above rejection addresses this claim limitation in that Schmitt et al. teaches increased production and renaturation of the polypeptides with the GG repeat sequences (paragraphs 0138-0140). Additionally, the examiner argues that since these GG repeat sequences share 100% sequence between the instant claims and those taught by applications 17/912,066 and 19/107,395, the increase in solubility, stability, and/or renaturation of the attached polypeptide is an inherent feature of the repeat sequences (See MPEP 2112.02).
The examiner does not find the arguments presented by the Applicant persuasive, and for these reasons, the rejections of record above apply.
Conclusion
14. Claims 12 and 14 are allowed. Claims 1-4, 6-9, 11, 13, 15, 17, 22, and 31 are rejected.
THIS ACTION IS MADE FINAL. 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.
15. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CIARA A MCKNIGHT whose telephone number is (703)756-4791. The examiner can normally be reached M-F 8:00am-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, Manjunath Rao can be reached on (571) 272-0939. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CIARA A MCKNIGHT/Examiner, Art Unit 1656
/SUZANNE M NOAKES/Primary Examiner, Art Unit 1656
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