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 Claims
Claims 1, 10, 16, 18-20, 22-23, 25-27, and 29-36, are presented. Claim 38 and 39 are new. Claims 16, 18-20, 22-23, 25-27, and 30-36 are withdrawn. Claims 1, 10, 29, and 38-39 are pending and under examination.
MAINTAINED REJECTIONS
Claim Rejections - 35 USC § 102
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 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.
Claims 1, 10, 29, and new claim 38, are 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).
Regarding claims 1, 10, 29 and 38: Kim taught use of double-stranded oligonucleotide comprising an RNA/RNA, DNA/DNA or DNA/RNA hybrid sequence, a double-stranded oligonucleotide structure comprising the double-stranded oligonucleotide, nanoparticle comprising the double-stranded oligonucleotide structure in the prevention or treatment of fibrosis or respiratory disease. (See Kim Abstract; also see Kim col. 7 lines 1-10). It is also noted that col. 7 of Kim, specifically pointed out idiopathic pulmonary fibrosis as required by the instant claims. (“[T]he present inventors selected amphiregulin as a gene associated with fibrosis including IPF, selected a double-stranded oligonucleotide that targets amphiregulin, and also identified an RNAi therapeutic agent capable of inhibiting amphiregulin expression”). Further, Fig. 12 of Kim showed decrease in expression of AREG when administered intravenously to mice with bleomycin-induced lung fibrosis with RNAi treatment. It is also known from Liu that bleomycin-induced lung fibrosis mimics IPF. (See Liu Abstract). It is noted that instant claims require that AREG is inhibited in AT2 cells of the lung. It is pointed out that the RNAi therapeutic agent when administered intravenously as described in Kim would inhibit AREG in any cell, including AT2 cells.
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, 10, 29 and 38 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: 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 inhibit AREG 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) 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) 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) 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 10 and 29 are rejected for their dependence on claim 1. It is also pointed out that although claim 10 is directed to a substance that inhibits the expression level of AREG in AT2 cells, the claim does not further limit the structure of the “substance” in any way.
Claims 1, 10, 29 and 38 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) administering a substance inhibiting Amphiregulin(AREG); and
b) inhibiting AREG in AT2 cells of lung 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; and wherein said substance inhibiting AREG is a substance inhibiting AREG in AT2 cells of lung from an animal or a human being.”
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.
However, Applicant’s experimental data does not support all the possible inhibitors of 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 prior art taught that it requires extensive experimentation to come up with an appropriate candidate as a lead molecule. 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 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. (See Specification [0142]). As such there is no “substance” described in the specification to inhibit AREG. 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.
Claims 10 and 29 are rejected for their dependence on claim 1.
Response to Arguments – 35 U.S.C. 102
Applicants argued that the Kim and Liu, each alone or in combination, fail to teach or suggest each and every element of the claimed invention. In particular, Kim and Liu both fail to identify AT2 cells as the relevant therapeutic target for IPF and that Kim instead directs the skilled person away from the specific, AT2-centric mechanism that underlies the present invention by focusing on AREG expression in mesenchymal cells and inflammation-driven disease models. The claimed method, which entails inhibiting AREG specifically in AT2 cells to treat progressive fibrosis, thus represents a distinct and novel departure from the prior art's teachings.
It is submitted that the claim does not require AT2 specific targeting of the inhibiting agent. Nor is the claimed method directed to specific methods of delivery that will sequester the inhibitory agent’s function in the AT2 cells. As such it is submitted that recitation that AREG is inhibited in AT2 cells merely recites a result inherent to AREG in lung tissue and does not impose a meaningful limitation distinguishing the claimed method from Kim.
Double Patenting
Claims 1, 10 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 and 10: 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, 10 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, 10 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 – 35 U.S.C. 112(a)
Applicants argued that the specification for the first time established a causal link between AREG expression in AT2 cells and development of idiopathic pulmonary fibrosis. Applicant contended that the invention lies in identifying the AT2-AREG pathway as a therapeutic target rather than in enumerating every possible substance capable of inhibiting AREG. The Applicant cited multiple genetic examples demonstrating that AREG overexpression in AT2 cells induced fibrosis and that deletion of AREG in AT2 cells attenuates disease progression thereby supporting the claimed method. Applicant submits that established RNAi and CRISPR techniques were routine at the time of filing and could readily be applied to AT2 cells without undue experimentation. The Applicant argued that the specification provides an enabling screening model and that enablement of a method claim does not require disclosure of every possible inhibitory substance.
Applicants’ arguments have been fully considered by are not persuasive.
It is reiterated that the test for written description “requires an objective inquiry into the four corners of the specification from the perspective of a person of ordinary skill in the art” and “[b]ased on that inquiry, the specification must describe an invention understandable to that skilled artisan and show that the inventor actually invented the invention claimed.” (See MPEP 1504). As such the disclosure external sources or post-filing evidence cannot be considered in evaluating written description. It is also pointed out that for enablement, the specification “must teach those skilled in the art how to make and use the full scope of the claimed invention without “undue experimentation.”” See MPEP 2601.01.III. Instant specification establishes a correlation between inhibition of AREG in AT2 cells to amelioration of IPF. However, the specification did not enable a person of ordinary skill in the art, nor did the specification have sufficient description for all possible “substance[s]” that inhibit AREG. It is submitted that the written description and enablement rejections stand even in view of the presented amendments. The claims remain overly broad, relative to the disclosure.
Response to Arguments – Double Patenting
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.
PNG
media_image1.png
18
19
media_image1.png
Greyscale
NEW REJECTIONS IN VIEW OF CLAIM AMENDMENTS
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 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.
Claim 39 requires the inhibitory substance of claim 1, which claim 1 requires to be an inhibitor of AREG, and for treatment of IPF, to be Gefitnib. It is however noted that the specification clearly teaches Gefitnib to be an inhibitor of EGFR, not AREG. (See Example 9). While the specification teaches that Gefitnib inhibits fibrosis development in lungs of mice, the molecule is not disclosed or taught to be an inhibitor of AREG. As such it is submitted that the specification fails to disclose the claimed invention.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
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.
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, Christopher M. Babic can be reached at 571-272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JAGAMYA NMN VIJAYARAGHAVAN/Examiner, Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633