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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 07/30/2026 has been entered.
Status of the Claims
Claims 1, 16, 18-20, 22-23, 25-27, 29-36, and 38-40, are presented. Claim 38 and 39 are new. Claims 16, 18-20, 22-23, 25-27, and 30-36 are withdrawn. Claims 1, 29, and 38-40 are pending and under examination.
Claim Objections
The amendment to the claims filed on July 30, 2026, does not comply with the requirements of 37 CFR 1.121(c) because the claim listing does not show markings to claims vis-à-vis their prior version. Amendments to the claims filed on or after July 30, 2003 must comply with 37 CFR 1.121(c) which states (emphasis added):
(c) Claims. Amendments to a claim must be made by rewriting the entire claim with all changes (e.g., additions and deletions) as indicated in this subsection, except when the claim is being canceled. Each amendment document that includes a change to an existing claim, cancellation of an existing claim or addition of a new claim, must include a complete listing of all claims ever presented, including the text of all pending and withdrawn claims, in the application. The claim listing, including the text of the claims, in the amendment document will serve to replace all prior versions of the claims, in the application. In the claim listing, the status of every claim must be indicated after its claim number by using one of the following identifiers in a parenthetical expression: (Original), (Currently amended), (Canceled), (Withdrawn), (Previously presented), (New), and (Not entered).
(1) Claim listing. All of the claims presented in a claim listing shall be presented in ascending numerical order. Consecutive claims having the same status of “canceled” or “not entered” may be aggregated into one statement (e.g., Claims 1–5 (canceled)). The claim listing shall commence on a separate sheet of the amendment document and the sheet(s) that contain the text of any part of the claims shall not contain any other part of the amendment.
(2) When claim text with markings is required. All claims being currently amended in an amendment paper shall be presented in the claim listing, indicate a status of “currently amended,” and be submitted with markings to indicate the changes that have been made relative to the immediate prior version of the claims. The text of any added subject matter must be shown by underlining the added text. The text of any deleted matter must be shown by strike-through except that double brackets placed before and after the deleted characters may be used to show deletion of five or fewer consecutive characters. The text of any deleted subject matter must be shown by being placed within double brackets if strike-through cannot be easily perceived. Only claims having the status of “currently amended,” or “withdrawn” if also being amended, shall include markings. If a withdrawn claim is currently amended, its status in the claim listing may be identified as “withdrawn—currently amended.”
(3) When claim text in clean version is required. The text of all pending claims not being currently amended shall be presented in the claim listing in clean version, i.e., without any markings in the presentation of text. The presentation of a clean version of any claim having the status of “original,” “withdrawn” or “previously presented” will constitute an assertion that it has not been changed relative to the immediate prior version, except to omit markings that may have been present in the immediate prior version of the claims of the status of “withdrawn” or “previously presented.” Any claim added by amendment must be indicated with the status of “new” and presented in clean version, i.e., without any underlining.
(4) When claim text shall not be presented; canceling a claim.
(i) No claim text shall be presented for any claim in the claim listing with the status of “canceled” or “not entered.”
(ii) Cancellation of a claim shall be effected by an instruction to cancel a particular claim number. Identifying the status of a claim in the claim listing as “canceled” will constitute an instruction to cancel the claim.
(5) Reinstatement of previously canceled claim. A claim which was previously canceled may be reinstated only by adding the claim as a “new” claim with a new claim number.
As noted above, the amendment under consideration herein fails to comply with 37 CFR 1.121 because the claim listing does not properly show mark-ups vis-à-vis the original claim text. Thus, the amendment could be considered non-responsive. However, in the interest of compact prosecution the amendment at issue will not be considered non-responsive, and has been entered. However, any future responses failing to comply with 37 CFR 1.121 will be held non-responsive, and will not be considered.
Claim 39 appears allowable, but is objected to for being dependent on a rejected base claim.
WITHDRAWN REJECTIONS
Claim Rejections - 35 USC § 102
Claims 1, 10, 29, and 38, were rejected under 35 U.S.C. 102(a)(2) as being anticipated by US12037589B2 (as supported by WO2019225968A1 filed May 22, 2019 and claiming priority to KR10-2018-0059783; May 25, 2018; hereinafter "Kim;" See PTO-892) as evidenced by Liu et al (Methods Mol Biol. 2017; hereinafter “Liu”; See PTO-892).
The rejection is withdrawn following claim amendments. Applicant’s amendments are drawn to particularly inhibiting AREG in AT2 cells, and the IPF being treated is specified as being specifically requiring upregulation of AREG in AT2 cells. It is pointed out that Kim did not teach, disclose or suggest the inhibition of AREG in AT2 cells, specifically, nor characterize the IPF in any specific way.
Claim Rejections - 35 USC § 112
Claims 39 is 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 rejection is withdrawn following claim amendments.
MAINTAINED 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.
Claims 1, 29, 38 and 40 stand rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement.
Regarding Claim 1, 29, 38 and 40: Applicant's specification is found enabling for delineating the relationship between Amphiregulin and pulmonary fibrosis. However, Applicant's specification is not found to be enabling for a method for treating IPF using any and all agents that knockout or silence or inhibit ARG-EGFR binding as currently claimed. It is again pointed out that the claims as currently worded encompass any substance that inhibits (either the activity or expression or any function of – as recited in claim 1) amphiregulin in AT2 cells as required by instant 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 carry out the method of the invention commensurate in scope with the current claims.
Analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention without undue or unreasonable experimentation. See Mineral Separation v. Hyde, 242 U.S. 261, 270 (1916). The key word is 'undue,' not experimentation.' " (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all these factors are considered, a sufficient number are discussed below so as to create a prima facie case.
Applicants' claims are directed to a substance that inhibits Amphiregulin in AT2 cells of the lung. The breadth of the claims includes siRNA, mRNA, small molecule and macro molecule inhibitors, peptides, oligonucleotides, among other therapeutics that work in AT2 cells.
The specification provides support for the generation of a fibrotic lung model in mice by knocking out cdc42 gene in AT2 cells. Additionally, it establishes that Amphiregulin (AREG) is strongly expressed in AT2 cells of Cdc42 AT2 null lungs after pneumonectomy (PNX) treatment. The specification also provides support for upregulation of AREG in AT2 cells of pulmonary fibrosis patients using ELISA. Overexpressing AREG in AT2 cells has been observed to be sufficient to induce lung fibrosis, as indicated in the specification. The specification provides a cre-lox system for knocking out the expression of amphiregulin and it was found that deleting Areg gene in Cdc42 null AT2 cells significantly attenuated the development of lung fibrosis. The specification finds that Areg gene is not essential for the survival and development of mice. Specification described that fibrotic mice treated with an inhibitor of EGFR, Gefitnib, from post-PNX day 6 to post-PNX day 30 (Figure 13A) and found that Gefitnib treatment also significantly inhibits the fibrosis development in the lungs of Cdc42 AT2 null mice. The specification suggests that inhibition of Areg is beneficial to treatment of pulmonary fibrosis.
At the time the invention was made many different approaches were known for discovery of drug to inhibit expression of proteins. For example, Gershell et al (Nat Rev Drug Discov. 2003 Apr, See PTO-892 of 04/18/2025) taught that Chemical compounds, use of “omic” libraries as starting points for development of drugs. Gershell also indicated pitfalls, and difficulties in development of drugs. “For many diseases, the most obvious approaches to cures have been tried and have often failed. The challenge now is for scientists to attack major diseases with fresh ingenuity. The broader swathes of intellectual property coverage around lead structures, as well as revenue losses from marketed drugs coming off patent, accentuate this demand.” (See Gershell et al, col. 1, para 1). The difficulties of generating new drugs is also shared by other scientists. For example, Pan taught that “[D]despite advances in technology, drug discovery is still a lengthy, expensive, difficult, and inefficient process, with a low rate of success.” (See Pan Abstract). As such the prior art underscores the effort and time involved in developing new therapeutics. Additionally, the prior art taught that several approaches are available for generating a lead molecule. For example, Gershell et al taught that natural compounds can be used to develop therapeutics (for example Penicillin) (See Gershell et al, col. 2, paragraph 1). Pan et al (J Pharm Pharm Sci. 2010, See PTO-892 of 04/18/2025) Recombinant proteins and monoclonal antibodies have greatly enriched our therapeutic armamentarium, which have become the leading area of expansion in the biologic segment within the pharmaceutical industry. Genome sciences, combined with bioinformatics tools, allow us to dissect the genetic basis of multifactorial diseases and to determine the most suitable drug targets. (See Pan et al; p. 463, col. 1, para 1). Hughes et al (Br J Pharmacol. 2011 Mar; See PTO-892 of 04/18/2025) taught that after a particular druggable target is selected, a lead is selected and optimized, and followed by testing. (See Hughes et al, Figure 1). National Academies Press (2014 Feb 6. 2, Drug Development Challenges, See PTO-892) taught that the lead can be a protein, DNA or RNA and that potential compounds, for example, can be generated through binding/functional, biochemical, and cellular or cytotoxicity assays. (See National Academies Press, p. 1, last paragraph)
Therefore, there was a recognized level of unpredictability with regards to how and what an inhibitor might be or its identity. Additionally, as suggested by the prior art, it requires extensive experimentation to come up with an appropriate candidate as a lead molecule.
Due to the lack of teachings in the art regarding a suitable inhibitor of Areg, and the recognized unpredictability in the area of drug discovery, a large amount of guidance and teachings would be necessary in order to be enabling for methods of such.
Guidance and teachings provided by Applicants in the instant specification is limited to disclosure that a “substance” that inhibits AREG. As such there is no guidance about any properties or structure of the “substance” other than its function to inhibit AREG. The Examples of the specification do not provide any guidance for a person of ordinary skill to arrive at an appropriate “substance” as required by claim 1. The Examiner acknowledges that the Office does not require the presence of working examples to be present in the disclosure of the invention (see MPEP §2164.02). However, in light of the state of the art, discussed above, which recognizes a high level of unpredictability and uncertainty in the field of drug discovery, and limited teachings in the specification with regards to the “substance”, the Office would require appropriate disclosure to support the “substance” for inhibition of AREG. The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). Thus, due to the high level of unpredictability in the art, the current specification would have to provide greater amounts of teachings and guidance directed to methods of carrying out the claimed invention.
Therefore, due to the sum of all the aforementioned factors, one of ordinary skill in the art, at the time the invention was made, would not expect to arrive at a substance for inhibition of AREG. Given that the art recognizes the uncertainty and unpredictability of arriving at an appropriate effector molecule, and that the Applicant has failed to demonstrate a specific substance for producing such an effect, the skilled artisan would be faced with the impermissible burden of undue experimentation in order to practice the claimed invention. Accordingly, claim 1 is deemed properly rejected.
Claims 29, 38 and 40 are rejected for dependence on claim 1.
Response to Arguments:
Applicants argued that claim 1 is directed to a method rather than a specific product and that enablement therefore requires only that a person of ordinary skill in the art be able to perform the recited steps without undue experimentation. It is noted that it is not disputed that claim 1 is directed to a method. However, the enablement requirement applies equally to method claims and the specification enable full scope of the claimed invention. The issue presented by claim 1 is not whether the specification enables one embodiment of treating IPF but whether it enables the full scope of the recited method, which encompasses administration of any substance comprising means of blocking the interaction between AREG and EGFR as well as knocking out or silencing the AREG in AT2 cells.
The working examples demonstrate genetic deletion and EGFR inhibitor Gefitnib treatment. This demonstrates that the inventors successfully performed those specific embodiments. However, claim 1 is not limited to the indicated embodiments. Rather, it encompasses any substance capable of blocking the interaction between AREG and EGFR, including antibodies, peptides, aptamers, small molecules and other structurally unrelated agents. The specification neither discusses representative species commensurate with the scope of the claim or provide a methodology to arrive at the all the recited/encompassed substances. The demonstration in Example 9 of treatment of IPF using gefitnib amounts to disclosure of a single agent, and does not enable a claim encompassing every substance capable of blocking AREG binding to EGFR.
Application relied upon Examples 6-8 for knocking out or silencing limitation. The Office agrees that the specification adequately describes conditional knockout of AREG gene in AT2 cells. However, the specification does not teach or exemplify silencing of the AREG gene. Gene silencing encompasses numerous mechanistically distinct approaches, including RNA interference, antisense oligos, CRISPR interference. The specification provided no working examples or sufficient guidance demonstrating these embodiments in AT2 cells for treatment of IPF. Accordingly, the specification does not fully enable silencing embodiment without undue experimentation.
Claims 1, 29, 38 and 40 stand 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.
Claim 1 states that:
“A method for treating idiopathic pulmonary fibrosis (IPF), comprising:a) knocking out or silencing the AREG gene in AT2 cells; or,b)_administering a substance comprising means for blocking the binding of AREG in AT2 cells to the EGFR receptor in lungs from an animal or a human being wherein IPF is characterized in that the expression level of AREG is up-regulated in AT2 cells of lung from an animal or a human being suffering from progressive fibrosis”
This claimed method encompasses any potential substance that can inhibit AREG. As such as indicated above, the “substance” encompasses for example, siRNA, mRNA, small molecule and macro molecule inhibitors, peptides, oligonucleotides, among other therapeutics that work in AT2 cells.
Additionally, claim 16 states: “A substance that blocks the binding of AREG to the EGFR receptor in a transgenic mouse, wherein AREG is specifically overexpressed in AT2 cells of lungs”
This claimed substance encompasses any potential substance that can blocks the binding of AREG to the EGFR receptor.
However, Applicant’s experimental data does not support all the possible inhibitors of amphiregulin in AT2 cells, at least even those enumerated above. It is clear that additional experimentation would be necessary to practice the full scope of the claimed invention. As indicated above the Applicants taught the genetic knockout of AREG in AT2 cells and Gefitnib as methods to treat IPF. However, the term “substances encompasses a family of structurally, and functionally diverse agents that have no support in the specification. Thus, Applicants were not in possession of the full scope of the claimed invention at the time of filing of the instant invention.
The specification as filed does not provide sufficient evidence that Applicants were in possession of the full scope of the claimed invention at the time of filing of the instant invention. For example, the Applicants only indicated that, Gefitnib, from post-PNX day 6 to post-PNX day 30 (Figure 13A) and found that Gefitnib treatment also significantly inhibits the fibrosis development in the lungs of Cdc42 AT2 null mice. (See Specification [0142]). It is submitted that the specification as filed does not provide sufficient evidence that Applicants were in possession of the full scope of the claimed invention at the time of filing. Therefore, due to the need for further experimentation to determine those parameters for a given polypeptide, it remains that it is the examiner’s position that the full scope of the claimed invention was not disclosed as of the filing date of the instant specification.
It is also pointed out that the specification demonstrates possession of conditional knockout of AREG gene in AT2 cells through a Cre-lox strategy. However, the specification contains no disclosure of silencing the AREG gene, including but not limited to RNA interference, siRNA, shRNA or any other technique for suppressing gene expression. Gene knockout and gene silencing are distinct biological mechanisms. As such the claimed embodiments at the time of filing lacks written description for silencing.
Claims 29, 38 and 40 are rejected for their dependence on claim 1.
Double Patenting
Claims 1, and 29 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of copending Application No. 17/935,400 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because of the reasons below.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claims 1: Claim 1 ‘400 application teaches an Amphiregulin antibody. It is noted that the application does not explicitly state that the Amphiregulin binds Amphiregulin in AT2 cells, however, it is expected by a person of ordinary skill in the art that any amphiregulin antibody will bind amphiregulin expressed in AT2 cells.
Regarding claim 29: Claim 2 of ‘400 application teaches that the Amphiregulin antibody binds human amphiregulin.
Claims 1, and 29 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 7-10, 12, 15, 18-20,22, 25-26, 29-31, 33, 35-36 of copending Application No. US18/688,572 (reference application).
Regarding claims 1, 16 and 29: Claim 1 ‘572 application teaches an Amphiregulin binding fusion protein. It is noted that the application does not explicitly state that the Amphiregulin binds Amphiregulin in AT2 cells, however, it is expected by a person of ordinary skill in the art that any amphiregulin antibody will bind amphiregulin expressed in AT2 cells. Further it is noted from the specification of the ‘572 application that the antibody inhibits AREG and reduces expression levels of AREG in mice (See [0006] of the reference application).
Response to Arguments
Applicants argued that the present application has an effective filing date of May 30, 2019, which is earlier than the effective filing date of March 27, 2020, for the 17/935,400 Application (or 09/30/2021 of US18/688,572). Consequently, pursuant to M.P.E.P. § 1490(VI)(D) this rejection should be withdrawn.
It is submitted that according to MPEP 804(I)(B)(1)(b)(i) and MPEP 1490(VI)(D)(2)(a), a provisional nonstatutory double patenting rejection is only withdrawn when it is the only rejection remaining in an application having the earliest effective U.S. filing date (taking into account any benefit under 35 U.S.C. 120, 121, 365(c), or 386(c) ) with respect to the conflicting claims); at which point the "provisional" nonstatutory double patenting rejection in the other (later filed) application(s) will be converted into a nonstatutory double patenting rejection when the application with the earliest U.S. effective filing date issues as a patent.
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Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAGAMYA VIJAYARAGHAVAN whose telephone number is (703)756-5934. The examiner can normally be reached 9:00a-5:00p.
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/JAGAMYA NMN VIJAYARAGHAVAN/Examiner, Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633
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