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 .
Application Status
The amended claims filed June 15, 2026 with the Response to the non-final Office Action are acknowledged. Claims 1-7, 9-13, 15-18, 20, and 22 are amended. Claim 8 has been canceled. Claim 23 is newly added.
Claims 1-7, 9-18, 20, and 22-23 are pending and under examination herein.
Priority
Acknowledgment is made of Applicant’s claim for foreign priority under 35 U.S.C. 119(a)-(d). The certification of the English translation of the foreign priority document, filed June 15, 2026, is accepted by the Examiner. Applicant is entitled to the foreign priority date of the CN202011425866.9 application filed on December 9, 2020.
Nucleotide and/or Amino Acid Sequence Disclosures
Applicant’s amendment(s) to the specification and substitute Sequence Listing place the application in compliance with the Requirements for Patent Applications Containing Nucleotide and/or Amino Acid Sequence Disclosures.
WITHDRAWN OBJECTIONS AND REJECTIONS
The objections to the specification, title, and abstract are withdrawn in view of Applicant's amendments thereto.
All prior rejections to claim 8 are rendered moot by the cancelation of the claim.
The objection to claim 12 is withdrawn in view of Applicant's amendments to the claim.
The rejection of claims 1-7, 9-18, 20, and 22 under 35 U.S.C. § 112(b) are withdrawn in view of Applicant's claim amendments.
The rejection of claims 1-7, 9-18, 20, and 22 under 35 U.S.C. § 112(a) as failing to comply with the written description requirement is withdrawn in view of Applicant's amendments to claims 1 and 2.
The rejection of claims 1-4, 9-10, 13-16, 18, 20, and 22 under 35 U.S.C. § 102(a)(2) as being anticipated by Ren (US 2022/0160766 A1) is withdrawn in view of Applicant's submission of a certified copy of the English translation of the foreign priority document and Applicant's arguments with respect to the timing of relevant disclosures by Ren. Remarks at pages 24-25. The rejections of claims 1, 5-7, 11-12, and 17 under 35 U.S.C. § 103 as being unpatentable over Ren (US 2022/0160766 A1) further in view of Goldman (Frontiers in Immunology (2017) 8: Article 865) and Rossotti (Biochemical Journal (2019) 476: 39-50) or further in view of Zhang (WO 2019/014891 A1) are withdrawn for the same reasons.
Rejoinder
The elected species of anti-EGFR and EGFRvIII single-domain antibody or antigen-binding fragment “S008-NB148-13”, comprising three CDRs corresponding to SEQ ID NOs: 72-74, respectively, under IMGT analysis, SEQ ID NOs: 75-77, respectively, under Kabat analysis, and SEQ ID NOs: 78-80, respectively, under Chothia analysis, and a VHH sequence of SEQ ID NO: 21, has been searched and is considered to be free of the prior art.
The search was expanded to the additional species recited in claims 1-2 as filed on June 15, 2026. The additional species are also found to be free of the prior art.
All species have been rejoined.
Pursuant to the procedures set forth in MPEP § 821.04(a), the restriction requirement
among the elected species of single-domain antibodies that specifically bind to EGFR and EGFRvIII, as set forth in the Office action mailed on December 22, 2025, is hereby withdrawn and claims 1-7, 9-18, 20, and 22-23 are fully examined herein for patentability under 37 CFR 1.104. In view of the withdrawal of the restriction requirement, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present patenting rejections over the claims of the instant application. Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
NEW OBJECTIONS AND MAINTAINED REJECTIONS
Claim Objections
Claims 1-7, 9-18, 20, and 22-23 are objected to because of the following informalities: The language of claim 1 should be amended to more clearly describe the claimed invention. In particular, the body of the claim would be clearer if the claim recited “…wherein the single-domain antibody or the antigen-binding fragment comprises a combination of CDRs, wherein the combination of CDRs comprises CDR1, CDR2, and CDR3; and wherein the CDR1, CDR2, and CDR3 are selected from the group consisting of: …”. In addition, the second-to-last member of the group of alternatives should include a conjunction (i.e., “and” or “or”) prior to the recitation of the last alternative in the group.
Claims 2-7, 9-18, 20, and 22-23, which depend from claim 1, are similarly objected to.
It is noted that the listing of combinations of three CDR sequences as set forth in claim 2 provides a clear and concise means of presenting the subject matter recited in claim 1 in tabular form. The use of tables in claims is generally reserved for when there is not a practical way to otherwise define the invention in words.
Appropriate correction is required.
Applicant is further advised that should claim 1 be found allowable, claim 2 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
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 2 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. This is a maintained rejection that has been updated to reflect Applicant's claim amendments.
Claim 2 recites the single-domain antibody or the antigen-binding fragment of claim 1, wherein the three CDRs comprise a combination of sequences as set forth in one of (1) through (66). These limitations are substantially identical to those recited in claim 1 and thus fail to further limit the claimed subject matter.
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.
Response to Arguments
Applicant's arguments filed June 15, 2026 have been fully considered but they are not persuasive.
Applicant argues that because claim 1 recites that “…the CDR1, CDR2, and CDR3 have any sequence combination selected from the following…” and then includes a table providing 66 CDR1 sequences, 66 CDR2 sequences, and 66 CDR3 sequences, the broadest reasonable interpretation of the claim includes “a single-domain antibody or antigen-binding fragment having one of the 66 possible CDR1 sequences, one of the 66 possible CDR2 sequences, and one of the 66 possible CDR3 sequences”. Applicant states that this is in contrast to claim 2 which recites “specific combinations of CDR1, CDR2, and CDR3 sequences” as set forth in (1), (2), etc.
In response, it is disputed that the broadest reasonable interpretation of claim 1 is a single-domain antibody having “mixed and matched” combinations of CDRs selected from the table presented in the claim. It is held that a reasonable person reading the claim would recognize that (1) the claimed single-domain antibody requires a combination of three CDRs (CDR1, CDR2, and CDR3), consistent with Applicant's interpretation, and (2) that each row in the table, which represents a specific embodiment of a VHH of the invention, likewise comprises a discrete combination of three CDRs as required by the claim (CDR1, CDR2, and CDR3). The claim does not recite, for example, that the anti-EGFR/EGFRvIII single-domain antibody or antigen-binding fragment comprises a combination of CDRs wherein CDR1 is selected from any one of SEQ ID NOs: 63, 66, 69, 72, etc. (or selected from any one of the sequences in the “CDR1” column of the table), wherein CDR2 is selected from any one of SEQ ID NOs: 64, 67, 70, 73, etc. (or selected from any one of the sequences in the “CDR2” column of the table), and wherein CDR3 is selected from any one of SEQ ID NOs: 65, 68, 71, 74, etc. (or selected from any one of the sequences in the “CDR3” column of the table), which would be more consistent with Applicant's interpretation.
Accordingly, the scope of claims 1 and 2 as written is considered to be materially the same and the rejection is maintained.
Claim Rejections - 35 USC § 112(a)
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 20 and 23 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating a tumor disease or inflammatory disorder associated with EGFR overexpression by administering a single-domain antibody of claim 1, does not reasonably provide enablement for preventing a tumor disease or an inflammatory disease, regardless of EGFR overexpression by administering a single-domain antibody or an antigen-binding fragment of claim 1. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. This is a maintained rejection that has been updated to reflect Applicant's claim amendments.
The amount of guidance, direction, and exemplification disclosed in the specification, as filed, would not be sufficient to enable the skilled artisan to use the claimed invention at the time the application was filed without undue experimentation. MPEP § 2164.01 states: “The standard for determining whether the specification meets the enablement requirement was cast in the Supreme Court decision of Mineral Separation v. Hyde, 242 U.S. 261, 270 (1916) which postured the question: is the experimentation needed to practice the invention undue or unreasonable? That standard is still the one to be applied. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). Accordingly, even though the statute does not use the term "undue experimentation," it has been interpreted to require that the claimed invention be enabled so that any person skilled in the art can make and use the invention without undue experimentation. In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404 (Fed. Cir. 1988).”
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue”. These factors, which have been outlined in the Federal Circuit decision of In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), include, but are not limited to, the nature of the invention, the state of the prior art, the relative skill of those in the art, the amount of direction or guidance disclosed in the specification, the presence or absence of working examples, the predictability or unpredictability of the art, the breadth of the claims, and the quantity of experimentation which would be required in order to practice the invention as claimed. See also Ex parte Forman, 230 USPQ 546 (BPAI 1986).
Nature of the invention / Breadth of the claims. The method of claims 20 and 23 is drawn to treating and/or preventing a tumor disease or an inflammatory disease associated with EGFR overexpression, comprising the step of administering an effective amount of the antibody or antigen-binding fragment of claim 1 to a patient in need thereof.
State of the prior art / Predictability of the prior art. Overexpression of EGFR (HER-1) and/or EGFRvIII has long been understood in the art to be implicated in various cancers, including breast cancer, non-small cell lung cancer (NSCLC), head and heck squamous cell carcinoma (HNSCC), glioblastoma multiforme, and others. Anti-EGFR antibodies have shown promise as a treatment strategy in these conditions. Consider, for example, the work of Atalay (Annals of Oncology (2003) 14(9): 1346-1363; cited in IDS); Modjtahedi (British Journal of Cancer (1996) 73: 228-235; cited in IDS); Kuan (Endocrine-Related Cancer (2001) 8: 83-96; cited in IDS); and Bianco (International Journal of Biochemistry & Cell Biology (2007) 39: 1416-1431; cited in PTO-892 mailed March 2026). However, Dubé (Journal of Clinical Investigation (2012) 122(8): 2780-2792; cited in PTO-892 mailed March 2026) notes that EGFR inhibition is not universally efficacious, as “resistance to EGFR inhibition occurs in tumors with mutant BRAF or KRAS” (Introduction).
Clinical trials aimed at proving preventative cancer activity by a specific intervention are largely infeasible, due to the impossibly large number of subjects and an equally impossibly long timeframe. Although cancer is a common disease, specific types of cancer are still relatively infrequent events in an otherwise healthy population. Therefore, trials with cancer incidence as endpoints would necessarily involve several thousands of subjects followed for several decades. Such logistic difficulties have precluded cancer prevention trials with cancer incidence as an endpoint in all but a select few malignancies with treatments such as tamoxifen and finasteride. See review by Lee (Nature Reviews Cancer (2011) 11: 211-218; cited in PTO-892 mailed March 2026) at page 211; Cancer Prevention Overview ((PDQ®)–Patient Version, National Cancer Institute; cited in PTO-892 mailed March 2026).
With respect to inflammatory disorders, which cover a broad range of conditions, the teachings of the art are less predictable. Wang (American Journal of Translational Research (2019) 11(2): 520-528; cited in PTO-892 mailed March 2026) teaches that EGFR is upregulated in psoriatic lesions, and that EGFR inhibition improves this phenotype (e.g., Abstract; pages 522-525; Figures 2 and 4; Table 1). Chen (Scientific Reports (2019) 9: 2516; cited in PTO-892 mailed March 2026; see whole document) teaches that use of the EGFR inhibitor afatinib (a small molecule inhibitor) attenuates oxygen/glucose deprivation (OGD)-induced neuroinflammation. By contrast, Dubé (supra) teaches that human inflammatory bowel disease (IBD) patients have reduced EGFR signaling, suggesting that impaired EGFR contributes to disease etiology (e.g., Introduction). Wang (e.g., page 523), Holcmann (Molecular & Cellular Oncology (2015) 2(4): e104969; cited in PTO-892 mailed March 2026; see whole document) and Perez-Soler (The Oncologist (2005) 10(5): 345-356; cited in PTO-892 mailed March 2026; see whole document) disclose that while use of EGFR inhibitors, including anti-EGFR antibodies, in cancer therapy shows clinical benefit for cancer, this treatment also promotes inflammation and dermatologic rashes.
Similarly to tumor diseases, the art does not seem to recognize EGFR inhibition as an established preventative agent for inflammatory diseases.
Working examples / Guidance in the specification. The specification discloses the generation of single-domain antibodies against human EGFR, which were prepared by immunizing two alpacas against human EGFR and recovering and screening single-domain antibodies of interest (Examples 1-2, pages 35-52). Twenty-two antibody clones were obtained, the VHH amino acid sequences of which are summarized in Table 2 (pages 38-40) and the corresponding three CDR sequences (according to IMGT, Kabat, and Chothia numbering schemes, respectively) are summarized in Table 4 (pages 44-46). Applicant determined that a VHH-Fc antibody construct comprising the antibody corresponding to S008-NB148-13 (as elected on February 13, 2026) binds to human EGFR, human EGFRvlll, murine EGFR, and monkey EGFR (e.g., Examples 4-6; Tables 11-15; Figures 10-12 and 14-15). Each of the single-domain antibodies comprising the CDR amino acid sequences of SEQ ID NO: 72-74, respectively, SEQ ID NO: 75-77, respectively, and SEQ ID NO: 78-80, respectively, are drawn to a single embodiment having a VHH comprising the amino acid sequence of SEQ ID NO: 21.
While the disclosure does set forth that the nanobodies® of the invention do bind to EGFR expressed in tumor cell lines (e.g., A431 cells as shown in Figure 17A) and would be expected to inhibit EGFR activity (e.g., Figure 21), the working examples do not include experiments illustrating that the antibodies of the invention were directly tested for their anti-tumor activity or anti-inflammatory activity in any disease model for these respective conditions. The working examples also do not provide a showing that the antibodies may be used as a preventative agent for either a tumor-related disease or an inflammatory disease.
Conclusion. Upon careful consideration of the factors used to determine whether undue experimentation is required, the amount of guidance, direction, and exemplification disclosed in the specification, as filed, is not deemed sufficient to have enable the skilled artisan to use the claimed invention at the time the application was filed to prevent any tumor disease or any inflammatory disease associated with EGFR overexpression, without undue and/or unreasonable experimentation.
Response to Arguments
Applicant's arguments filed June 15, 2026 have been fully considered but they are not persuasive.
Applicant submits that the specification is enabling for treating a tumor disease or inflammatory disorder associated with EGFR overexpression by administering the single-domain antibody of claim 1.
In response, while the Applicant's amendments address the grounds of rejection related to the treatment of an EGFR overexpressing cancer or inflammatory disease, the amendment does not address the grounds of rejection related to prevention of such a cancer or inflammatory disease. As set forth above, the state of the art recognizes that these conditions are not preventable, and Applicant's disclosure does not provide a showing that the instantly claimed single-domain antibodies prevent tumors or inflammatory diseases associated with EGFR overexpression.
Accordingly, the rejection is maintained.
Conclusion
No claims are allowed.
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.
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/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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