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 .
Election/Restrictions
Applicant's election with traverse of Group 1 (a recombinant protein and products comprising it, claims 1-6 and 12-14) and the species of SEQ ID NOs: 13 and 14 in the reply filed on 13 July 2026 is acknowledged.
The traversal is on the ground(s) that “M.P.E.P. §803 requires a showing of burden on the search and it is believed that the claims of the present application would be part of an overlapping search area. Furthermore, electronic searching allows for a search of many, or theoretically all, relevant subclasses without substantial additional effort. Accordingly, Applicant respectfully traverses the Restriction Requirement on the grounds that a search and examination of the entire application would not place a serious burden on the Examiner, whereas it would be a serious burden on Applicant to prosecute and maintain separate applications.” This is not found persuasive because the search burden required my MPEP 803 was addressed in the Restriction Requirement (see final para. of pg. 3 and the third para. of pg. 5) and the arguments have not persuaded the examiner that there would not be a serious search burden.
The requirement is still deemed proper and is therefore made FINAL.
Claim Status
The amended claim set filed 30 Mar 2026 is acknowledged. Claims 1-18 are currently pending. Of those, claim 1 is currently amended, and no claims are new. Claims 7-11 and 15-18 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 13 July 2026. No claims are cancelled. Claims 1-6 and 12-14 will be examined on the merits herein.
Priority
The instant application claims priority to CN202110908697.2 (filed 9 Aug 2021), PCT/CN2022/110916 (8 Aug 2022) and is a CIP of 18/069,265 (21 Dec 2022). Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. 18/069,265, filed on 28 Apr 2023. However, the foreign priority document is not in English, so support cannot be assessed for the claimed invention. The effective filing date used to search 1-6 and 12-14 is 8 Aug 2022.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 16 Aug 2024 and 14 Feb 2025 were filed in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner. Signed copies of these statements are attached with this action. The reference copies not included with in this case can be found in parent application 18/069,265.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 3 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 1 recites “wherein said spacer peptide comprises 2 EAs (Glu Ala Glu Ala, SEQ ID NO: 8).” Claim 3 depends from claim 1 and also recites “wherein said spacer peptide comprises an amino acid sequence as shown in SEQ ID NO: 8.” As both claims 1 and 3 recite that the spacer peptide comprises SEQ ID NO: 8, claim 3 does not further limit claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-6 and 12-14 are rejected under 35 U.S.C. 103 as being unpatentable over Sun et al. (US-20190352345-A1; hereafter Sun; IDS filed 16 Aug 2024) in view of Emberson et al. (2005; hereafter Emberson; made of record in IDS filed 16 Aug 2024).
Regarding claims 1-2 and 5-6, Sun teaches rLZ-8 mutants [Abstract]. Sun teaches a D70K rLZ-8 mutant that has increased tumor inhibitory effects relative to the LZ-8 control group [0032]. The sequence listing states that SEQ ID NO: 1 is “The original sequence of the mutants… from the immunoregulatory protein of Ganoderma lucidum.” Alignment 1 below demonstrates that the Sun SEQ ID NO: 1 is identical to instant SEQ ID NO: 13 except at position 70 where SEQ ID NO: 13 has a D-to-K mutation, so the Sun D70K mutant is identical to SEQ ID NO: 13. Alignment 2 demonstrates that the D70K mutant is identical to SEQ ID NO: 14 except that it lacks an N-terminal EAEA spacer sequence. Sun teaches the mutants can be recombinantly expressed in Pichia pastoris [0065].
Regarding claims 12-14, Sun teaches that mice are administered an rLZ-8 composition [0143], and that the D70K mutant was administered in this way [0146]. Therefore, Sun teaches a pharmaceutical composition comprising the protein, and to administer the purified composition it must be present in some sort of container (i.e. a kit, see instant [0134] which defines a kit can be the recombinant protein in a single container). Also, for claim 20, it is noted that [instant 0073] defines the drug delivery device as comprising an infusion module in addition to the active ingredient. Sun teaches a drug delivery device by teaching combining the composition with the syringe (an infusion module) at the time of injecting.
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Alignment 1: of Sun SEQ ID NO: 1 with instant SEQ ID NO: 13. The sequences are identical except at position 70 where SEQ ID NO: 13 has a D-to-K mutation.
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Alignment 2: Alignment of SEQ ID NO: 14 with SEQ ID NO: 1 Sun et al. (US-20190352345-A1) in which a D70K mutation has been manually added. The proteins are identical except for the addition of the spacer sequence.
Sun does not teach adding a spacer peptide to the LZ-8 mutant that would result in EAEA being present at the N-terminus of the protein sequence, as required by claims 3-6.
Regarding claims 1 and 3-6, Emberson teaches a recombinant expression of a single chain antibody (scFv) in Pichia pastoris (Title). Specifically, Emberson compares two different expression constructs for recombinantly expression: a “CS” construct that has a complete α-MF secretory signal sequence that finishes with EKREAEA (i.e. a spacer peptide comprising SEQ ID NO: 8), and a “INCS” construct that has an incomplete α-MF secretory signal sequence that deletes EAEA and instead finishes with EKR (Table 1 on pg. 138). Both the CS and INCS sequences are located immediately N-terminal to the scFv (Table 1 on pg. 138). Emberson teaches that “The amount of scFv produced in the CS culture was clearly higher than from the INCS culture. This higher level of scFv expression was not clone-specific, since in a comparison of 10 clones of each construct, CS clones consistently expressed more scFv than INCS clones” (par. bridging pg. 144-145). Also, the CS construct is less heterogeneous when purified: it “migrates [on a gel] as a single band, whereas the purified INCS-anti-CD33scFv, although also migrating at the same MW, was present as a doublet of bands” (pg. 142 par. bridging cols. and Figure 3 on pg. 142). N-terminal sequencing data demonstrated that the EAEA tag (i.e. a spacer peptide comprising SEQ ID NO: 8) was retained at the N-terminus of the purified scFv (pg. 142 col. 2 par. 2 and Table 2 on pg. 143).
One of ordinary skill in the art at the time of filing would consider it prima facie obvious to improve the Sun LZ-8 mutant by adding a complete α-MF secretory signal sequence as taught by Emberson, thereby arriving at the claimed invention, because Emberson teaches the complete α-MF secretory signal sequence (which has EAEA immediately N-terminal to the protein product) increases the amount of protein produced and makes the purified product more homogenous. Therefore, the combination would be desirable to obtain these same advantages for the LZ-8 mutant protein. See MPEP 2144(II): “The strongest rationale for combining references is a recognition, expressly or impliedly in the prior art … that some advantage or expected beneficial result would have been produced by their combination.” This modification could be done with a reasonable expectation of success because both Sun and Emberson demonstrate the molecular biology techniques to generate a recombinant expression system in P. pastoris.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that applying a known technique to a known device, method or product ready for improvement is obvious because a particular known technique is recognized as part of the ordinary capabilities of one skilled in the art. In the instant case, Sun contains a “base” product of a recombinant D70K LZ-8 mutant that is produced in P. pastoris; and Emberson contains a similar method for recombinant expression of a protein in P. pastoris wherein the technique of using a complete secretory signal sequence that ends with EAEA is taught as advantageous. Thus, one of ordinary skill in the art would have recognized that applying the known technique taught by Emberson would have yielded predictable results (i.e. the same advantages) and an improved system.
When the Emberson complete signal sequence (“CS”), which ends with EAEA, is attached to the N-terminus of the D70K LZ-8 mutant of Sun, the combined product will comprise SEQ ID NO: 14 (see Alignment 2 above) and will have an N-terminal signal sequence comprising EAEA, SEQ ID NO: 8. Therefore, the claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
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 1-6 and 12-14 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 12,077,566 in view of Emberson et al. (2005; hereafter Emberson; made of record in IDS filed 16 Aug 2024).
Regarding instant claims 1-2 and 5-6, ‘566 claim 1 (and dependent claims) teaches a D70K rLZ-8 mutant, where the mutation is relative to SEQ ID NO: 1. ’56 claim 4 (and dependent claims) is a method of using the mutant to treat abnormal EGFR-expressing tumors. ‘566 is a patented version of the Sun Pre-Grant Publication above, so the alignments above demonstrates that the D70K mutant is identical to SEQ ID NO: 13 and almost identical to SEQ ID NO: 14 except that it lacks an N-terminal EAEA spacer sequence. ‘566 claim 2 teaches the mutant can be recombinantly expressed in a fungal expression system.
Regarding claims 12-13, ‘566 claims 3-9 teach composition comprising the protein mutant that can be administered to a subject, so the claims of ’56 teach pharmaceutical composition comprising the protein. ’566 claims 3 and 9 teach the protein can be formulated into injected solutions, so to administer the purified composition it must be present in some sort of container (i.e. a kit, see instant [0134] which states a kit can be the recombinant protein in a single container). ‘455 claim 9 recites oral administration which does not require any additional components other than the composition for drug delivery, so the composition itself is the drug delivery device. Also the claims of ‘455 teach a drug delivery device by teaching combining the composition with the syringe (an infusion module) at the time of injecting.
The claims of ‘455 do not teach adding a spacer peptide to the LZ-8 mutant that would result in EAEA being present at the N-terminus of the protein sequence, as required by claims 3-6.
Regarding claims 1 and 3-6, Emberson teaches a recombinant expression of a single chain antibody (scFv) in Pichia pastoris (Title). Specifically, Emberson compares two different expression constructs for recombinantly expression: a “CS” construct that has a complete α-MF secretory signal sequence that finishes with EKREAEA (i.e. a spacer peptide comprising SEQ ID NO: 8), and a “INCS” construct that has an incomplete α-MF secretory signal sequence that deletes EAEA and instead finishes with EKR (Table 1 on pg. 138). Both the CS and INCS sequences are located immediately N-terminal to the scFv (Table 1 on pg. 138). Emberson teaches that “The amount of scFv produced in the CS culture was clearly higher than from the INCS culture. This higher level of scFv expression was not clone-specific, since in a comparison of 10 clones of each construct, CS clones consistently expressed more scFv than INCS clones” (par. bridging pg. 144-145). Also, the CS construct is less heterogeneous when purified: it “migrates [on a gel] as a single band, whereas the purified INCS-anti-CD33scFv, although also migrating at the same MW, was present as a doublet of bands” (pg. 142 par. bridging cols. and Figure 3 on pg. 142). N-terminal sequencing data demonstrated that the EAEA tag (i.e. a spacer peptide comprising SEQ ID NO: 8) was retained at the N-terminus of the purified scFv (pg. 142 col. 2 par. 2 and Table 2 on pg. 143).
One of ordinary skill in the art at the time of filing would consider it prima facie obvious to improve the LZ-8 mutant from the claims of ’455 by adding a complete α-MF secretory signal sequence as taught by Emberson, thereby arriving at the claimed invention, because Emberson teaches the complete α-MF secretory signal sequence (which has EAEA immediately N-terminal to the protein product) increases the amount of protein produced and makes the purified product more homogenous. Therefore, the combination would be desirable to obtain these same advantages for the LZ-8 mutant protein. See MPEP 2144(II): “The strongest rationale for combining references is a recognition, expressly or impliedly in the prior art … that some advantage or expected beneficial result would have been produced by their combination.” This modification could be done with a reasonable expectation of success because Emberson demonstrates the molecular biology techniques to generate a recombinant expression system in P. pastoris.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that applying a known technique to a known device, method or product ready for improvement is obvious because a particular known technique is recognized as part of the ordinary capabilities of one skilled in the art. In the instant case, the claims of ‘455 contain a “base” product of a recombinant D70K LZ-8 mutant that is produced in yeast; and Emberson contains a similar method for recombinant expression of a protein in the yeast P. pastoris wherein the technique of using a complete secretory signal sequence that ends with EAEA is taught as advantageous. Thus, one of ordinary skill in the art would have recognized that applying the known technique taught by Emberson would have yielded predictable results (i.e. the same advantages) and an improved system.
When the Emberson complete signal sequence (“CS”), which ends with EAEA, is attached to the N-terminus of the D70K LZ-8 mutant of the claims of ‘941, the combined product will comprise SEQ ID NO: 14 (see Alignment 2 above) and will have an N-terminal signal sequence comprising EAEA, SEQ ID NO: 8. Therefore, the claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Lin (US-7601808-B2; PTO-892) teaches a recombinant LZ-8 sequence (SEQ ID NO: 9) that has the sequence “EAEA” N-terminal to the protein sequence [Figure 6]. Alignment 3 below compares it to instant SEQ ID NO: 13; it differs in not having the D70K mutation, having a spacer peptide comprising “EAEA” and having a C-terminal extension.
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Alignment 3 comparing instant SEQ ID NO: 13 with Lin SEQ ID NO: 9 (recombinant LZ-8).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMELIA N DICKENS whose telephone number is (571)272-0381. The examiner can normally be reached M-F 8:30-4:30 (EDT/EST).
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, Samira Jean-Louis can be reached at (571) 270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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AMELIA N DICKENS
Examiner
Art Unit 1645
/AMELIA NICOLE DICKENS/Examiner, Art Unit 1645
Prosecution Insights