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 .
Claim Status
Claims 1-20 are pending and currently under consideration for patentability under 37 CFR 1.104.
Priority
This application claims benefit of Provisional U.S. Application No. 63/479,685 filed on 01/12/2023. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Claims 1-20 have an effective filing date of 01/12/2023 corresponding to Provisional U.S. Application No. 63/479,685.
Information Disclosure Statement
The information disclosure statements filed on 12/24/2024 and 12/09/2025 have been considered. Signed copies are enclosed.
Notably, the disclosure statements filed on 12/24/2024 and 12/09/2025 list Search Reports. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
Claim Interpretation
For the purposes of claim interpretation, the phrase "mucus obstruction" in claims 1, 10, and 16 will be treated as mucus occluding airways to any degree.
For the purposes of claim interpretation, the phrases “intelectin-1 (ITLN-1) inhibitor” and “ITLN-1 inhibitor” in claims 1, 9, and 16 will be treated as any composition or molecule that lowers the activity or reduces expression of ITLN-1 to any degree.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2, 7, 10, and 15-20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 2, 10, and 17, the phrase “T2-high asthmatic subject” renders the claims indefinite because the threshold for a T2-high response in an asthmatic subject is unclear. T2-high is a subjective term. MPEP 2173.06(b) states: “Some objective standard must be provided in order to allow the public to determine the scope of the claim. A claim term that requires the exercise of subjective judgment without restriction may render the claim indefinite. In re Musgrave, 431 F.2d 882, 893, 167 USPQ 280, 289 (CCPA 1970).” The instant specification does not provide an objective standard for T2-high and thus is indefinite.
For the purposes of claim interpretation, the phrase “T2-high asthmatic subject” will be treated as any subject with asthma or asthmatic symptoms that experiences a T2-immune response to any degree.
Regarding claims 7, 15, and 20, the phrase “anti-intelectin molecule” renders the claims indefinite because it is unclear (i) what constitutes an anti-intelectin molecule and (ii) if intelectin refers to ITLN-1 alone or all intelectins.
For the purposes of claim interpretation, the phrase “anti-intelectin molecule” will be treated as any molecule, including but not limited to small molecules, RNA, DNA, antibodies, and antigen-binding fragments, that binds either to the protein ITLN-1 or genetic material, such as DNA and RNA, encoding the protein ITLN-1. Binding can occur directly or through downstream effects.
Regarding claims 7, 15, and 20, the phrase “anti-intelectin antibody” renders the claims indefinite because it is unclear if intelectin refers to ITLN-1 alone or all intelectins.
For the purposes of claim interpretation, the phrase “anti-intelectin antibody” will be treated as an antibody that binds either to the protein ITLN-1 or genetic material, such as DNA and RNA, encoding the protein ITLN-1.
Regarding claim 16, the phrase "for use in reducing mucus obstruction in a subject in need thereof" renders the claim indefinite because, since the claim does not set forth any steps involved in the method/process, it is unclear what method/process Applicant is intending to claim. Claims 17-20 are included in this rejection as they incorporate and/or depend on claim 16.
For the purposes of claim interpretation, the phrase "for use in reducing mucus obstruction in a subject in need thereof" will not hold patentable weight as it is directed to intended use.
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 1-20 are 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.
Claims 1-20 are drawn to a method of reducing mucus obstruction in a subject in need thereof comprising administering to the subject an intelectin-1 (ITLN-1) inhibitor (claims 1-8) or a pharmaceutical composition comprising ITLN-1 inhibitor (claims 9-20).
Instead of defining the inhibitor by its structure, the instant application uses the functional characteristic of inhibition of ITLN-1. An inhibitor is not one specific type of molecule. The following describes different types of inhibitors and their corresponding structures, mechanisms of action, and challenges in creation:
Antagonistic small molecules
Regarding antagonistic small-molecules, Cochran states “developing such molecules is far from trivial. Ideally, one wants not only high potency against the target protein, but also low toxicity, few side effects and good bioavailability “(Antagonists of protein–protein interactions, Chemistry & Biology, 2000, Pg. R85, column 2, ¶ 2, lines 2-5). These small molecules typically are less than 500 Da (Pg. R85, column 2, last ¶, lines 9-10), defined by their size than their structure. “[U]nderstanding molecular recognition of protein surfaces is a challenging physical chemistry problem” (Cochran, Pg. R87, column 1, ¶ 2, lines 1-2), as it is extremely unlikely that every surface of the target protein is suitable for binding of a small molecule. Taken together, Cochran establishes small molecule discovery as a difficult, unpredictable task.
Antagonistic antibodies
Regarding antagonistic antibodies, Sifniotis et al. state there are numerous formats to address challenges in antibody therapeutics including “[antibody-drug conjugates] as a targeted drug delivery system, bispecific and fragment mAb platforms for tailored engagement and increased bioavailability, and recombinant Fc-fusion proteins for an increased half-life and introduced immunological engagement” (Current Advancements in Addressing Key Challenges of Therapeutic Antibody Design, Manufacture, and Formulation, Antibodies, 2019, Pg. 14, ¶ 4, lines 3-5). Antibody formats are diverse with distinct structures and functions. For example, antibody fragments include “Fabs and single chain variable fragments (scFv)” (Pg. 9, ¶ 4, line 4) . These fragments show “better tissue penetration and biodistribution than whole mAb therapeutics; however, a pitfall of smaller peptides lacking an Fc region is a highly reduced in vivo half-life and poor retention times” (Sifniotis et al., Pg. 11, last ¶, lines 1-3). The term “antibody,” therefore, encompasses a variety of species, each with their own advantages and disadvantages.
Sevy and Meiler state “antibodies pose formidable challenges for protein structure prediction and design due to their large size and highly flexible loops in the complementarity-determining regions” (Antibodies: computer-aided prediction of structure and design of function, Microbiol Spectrum, 2014, Pg. 1, Abstract, lines 6-9). Consequently, an antibody’s structure cannot be predicted from function alone accurately i.e. stating the antibody binds ITLN-1 is not a sufficient description.
ITLN-1 antibodies in the prior art are used in immunohistochemistry (Yi et al., Intelectin contributes to allergen-induced IL-25, IL-33, and TSLP expression and type 2 response in asthma and atopic dermatitis, Mucosal Immunol, 2017, Pg. 12, ¶ 3, line 4, “immunohistochemistry with rabbit-anti-human intelectin”). There are no known biological inhibitors of ITLN-1.
Gene silencing
Aagaard and Rossi teach “there are a number of hurdles and concerns that must be overcome prior to making [RNA interference] a real therapeutic modality” (RNAi therapeutics: principles, prospects and challenges, Adv Drug Deliv Rev, Pg. 1, Abstract, lines 6-7), wherein gene silencing results from degradation of the mRNA encoding the target protein (Pg. 1, Abstract, lines 5-6, siRNA leads to “degradation of the target mRNA”). “Notably, efficacy… for individual target sites varies widely among siRNA [small interfering RNA]. Important criteria for siRNA efficacy include thermodynamic end stability, target mRNA accessibility, structural features and additional position specific determinants” (Aagaard and Rossi, Pg. 2-3, last ¶ Pg. 2 – first ¶ Pg. 3). In addition, siRNA is known to have off-target gene silencing; however, “predicting off targets the picture is far from complete as a large number of genes with good seed match remain unaffected” (Aagaard and Rossi, Pg. 7, ¶ 1, lines 6-8). These teachings indicate siRNA design is not straightforward.
In the CRISPR-Cas9 system, Roy et al. states guide RNA directs Cas9 to the target DNA site to knockout a gene (CRISPR/Cascade 9-Mediated Genome Editing-Challenges and Opportunities, Front Genet, 2018, Pg. 1, ¶ 2, lines 7-9, “Cascade 9 is a RNA guided dsDNA nuclease… is responsible for cleaving the targeted DNA”; Pg. 2, column 2, ¶ 1, line 4, “Candidate gene knockout” using CRISPR-Cas9); this method introduces insertions or deletions to stop gene expression (Roy et al., Pg. 2, column 1, ¶ 1, line 5, “resulting in deletions or insertions leading to loss of function”). Similar to siRNA, off-target gene silencing is a major challenge in CRISPR-Cas9 “as Cascade 9 may recognize sequences with up to 5 mismatched bases” (Roy et al. Pg. 6, column 2, last ¶, lines 1-3). Therefore, genetic knockdowns via CRISPR-Cas9 are not always effective and predictable.
The term “ITLN-1 inhibitor” encompasses a broad genus because inhibition can occur at the DNA level by reducing transcription of ITLN-1 (Roy et al, Pg. 2, column 1, ¶ 1, line 5, CRISPR-Cas9 system “resulting in deletions or insertions leading to loss of function” of the target gene), at the RNA level by degrading mRNA encoding ITLN-1 (Aagaard and Rossi, Pg. 1, Abstract, lines 5-6, siRNA leads to “degradation of the target mRNA”), or at the protein level by directly binding ITLN-1 to inhibit its activity (Cochran, Pg. R85, column 2, last ¶, line 4, small molecules are selected for “high potency against the target protein”; antagonistic antibodies bind antigens on proteins).
As such, claim 1-20 are drawn to a method of reducing mucus obstruction in a subject in need thereof comprising administering to the subject a genus of ITLN-1 inhibitors (claims 1-8) or a pharmaceutical composition comprising a genus of ITLN-1 inhibitors (claims 9-20).
The instant specification discloses ITLN-1 knockdowns in “tracheal airway epithelial basal cells through CRISPR-Cas9 targeting of the ITLN1 gene” (¶ 0076, Example 3) to correlate ITLN-1 expression with mucostasis in the airway, wherein the ITLN-1 inhibitor is the guide RNA and targets the ILTN1 gene at the DNA level (¶ 0057, describes CRISPR guide sequences to silence ITLN1 gene). The instant specification also includes analysis of ITLN-1 eQTL data (¶ 80, Example 5) to correlate ITLN-1 expression with T2 inflammation in asthmatic patients. There is no ITLN-1 inhibitor in this example.
The prior art discloses “Itln knockdown [in an asthmatic mouse model] reduced allergen-induced increases in… development of type 2 response, eosinophilic inflammation, mucus overproduction, and airway hyperresponsiveness” (Pg. 1, Abstract, lines 6-8), wherein the ITLN-1 is shRNA targeting mRNA encoding ITLN-1 (Synbio Technologies, siRNA’s RNA-Interfering Partner: shRNA, 2026, Pg. 2, ¶ 1, lines 8-9, shRNA after processing “binds to the target mRNA in a sequence-specific manner via complementary base pairing” for gene silencing).
However, Applicant is claiming a large and structurally diverse genus of ITLN-1 inhibitors. Absent empirical determination, one skilled in the art would be unable to immediately envision, recognize, or distinguish at least most of the members comprised within the genus claimed, specifically (i) if the inhibition is done at the DNA, RNA, or protein level and (ii) the identity of the inhibitor.
Accordingly, Applicant’s disclosure is not sufficient to demonstrate possession of the entire claimed antibody and Applicant’s disclosure does not satisfy the written description requirement of 35 U.S.C. 112(a).
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application, including “the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention” (MPEP 2163[II][A][2]).
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus.
A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. As previously indicated, Applicant has disclosed a species within the genus claimed (i.e. guide RNA used in a CRISPR-Cas9 system). However, given the large number of species encompassed by the genus claimed as well as the high level of structure variation that would be displayed by members of the claimed genus, the disclosure of one adequately described species is not sufficiently representative of the entire genus.
Furthermore, Applicant has not disclosed relevant, identifying characteristics of an ITLN-1 inhibitor that confer the ability to reduce transcription of ITLN-1, degrade mRNA encoding ITLN-1, or directly bind to ITLN-1 to inhibit its activity. Absent a description of the at least minimal structural features correlating with a functional ability to inhibit ITLN-1 which are shared by members of a genus of inhibitors, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish (i) if the inhibition is done at the DNA, RNA, or protein level and (ii) the identity of the inhibitor.
Although (i) screening techniques can be used to discover antibodies or small molecules that possess the ability to inhibit ITLN-1 and (ii) RNA sequences can be created through trial and error for gene silencing purposes, Applicant is reminded that the written description requirement of 35 U.S.C. 112 is severable from the enablement provision. As stated in Vas-Cath Inc. v. Mahurkar (CA FC) 19 USPQ2d 1111, 935 F2d 1555, “The purpose of the ‘written description’ requirement is broader than to merely explain how to ‘make and use’; the applicant must also convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.”
Accordingly given the difficulty associated with predicting ITLN-1 inhibitors, and given the lack of particularity with which the genus is described in the specification, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish at least most of the members of the genus to which the claims are directed, and therefore the instant disclosure fails to demonstrate that Applicant was in possession of the claimed invention at the time the application was filed.
University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that: To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention.” Lockwood v. American Airlines Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli , 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention" Lockwood, 107 F.3d at 1572, 41 USPQ2datl966.
The specification does not reasonably convey possession of the subject matter of claims 1-20. Claims 1-20 fail to comply with the written description requirement of 35 U.S.C. 112(a) as a person having ordinary skill in the art cannot reasonably conclude that the applicant had possession of the claimed invention at the time the instant application was filed.
Claims 1-8 and 16-20 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 (i) a method of reducing mucus occlusion of airways due to asthma in a subject in need thereof comprising administering to the subject shRNA (claims 1-8) and (ii) a pharmaceutical composition comprising shRNA for use in reducing mucus occlusion of airways due to asthma in a subject in need thereof (claims 16-20), does not reasonably provide enablement for (i) a method of reducing all mucus obstruction in a subject in need thereof comprising administering to the subject any ITLN-1 inhibitor (claims 1-8) and (ii) a pharmaceutical composition comprising any ITLN-1 inhibitor for use in reducing all mucus obstruction in a subject in need thereof (claims 16-20). 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.
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation’.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added). The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed most recently in Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008). See also In re Cortright, 49 USPQ2d 1464, 1466 and Bristol-Myers Squibb Co. v. Rhone-Poulenc Rorer Inc., 49 USPQ2d 1370.
The factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). Among these factors are: (1) the nature or the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary. When the above factors are weighed, it is the examiner’s position that one skilled in the art could not practice the invention without undue experimentation. Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
(1) The nature of the invention and (2) the state of the prior art
Claim 1 is drawn to “[a] method of reducing mucus obstruction in a subject in need thereof, comprising administering to the subject an intelectin-1 (ITLN-1) inhibitor” (lines 1-2). Claim 16 is drawn to “[a] pharmaceutical composition comprising an ITLN-1 inhibitor, for use in reducing mucus obstruction in a subject in need thereof” (lines 1-2).
Instead of defining the inhibitor by its structure, the instant application uses the functional characteristic of inhibition of ITLN-1. An inhibitor is not one specific type of molecule. The following describes different types of inhibitors and their corresponding structures, mechanisms of action, and challenges in creation:
Antagonistic small molecules
Regarding antagonistic small-molecules, Cochran states “developing such molecules is far from trivial. Ideally, one wants not only high potency against the target protein, but also low toxicity, few side effects and good bioavailability “(Antagonists of protein–protein interactions, Chemistry & Biology, 2000, Pg. R85, column 2, ¶ 2, lines 2-5). These small molecules typically are less than 500 Da (Pg. R85, column 2, last ¶, lines 9-10), defined by their size than their structure. “[U]nderstanding molecular recognition of protein surfaces is a challenging physical chemistry problem” (Cochran, Pg. R87, column 1, ¶ 2, lines 1-2), as it is extremely unlikely that every surface of the target protein is suitable for binding of a small molecule. Taken together, Cochran establishes small molecule discovery as a difficult, unpredictable task.
Antagonistic antibodies
Regarding antagonistic antibodies, Sifniotis et al. state there are numerous formats to address challenges in antibody therapeutics including “[antibody-drug conjugates] as a targeted drug delivery system, bispecific and fragment mAb platforms for tailored engagement and increased bioavailability, and recombinant Fc-fusion proteins for an increased half-life and introduced immunological engagement” (Current Advancements in Addressing Key Challenges of Therapeutic Antibody Design, Manufacture, and Formulation, Antibodies, 2019, Pg. 14, ¶ 4, lines 3-5). Antibody formats are diverse with distinct structures and functions. For example, antibody fragments include “Fabs and single chain variable fragments (scFv)” (Pg. 9, ¶ 4, line 4) . These fragments show “better tissue penetration and biodistribution than whole mAb therapeutics; however, a pitfall of smaller peptides lacking an Fc region is a highly reduced in vivo half-life and poor retention times” (Sifniotis et al., Pg. 11, last ¶, lines 1-3). The term “antibody,” therefore, encompasses a variety of species, each with their own advantages and disadvantages.
Sevy and Meiler state “antibodies pose formidable challenges for protein structure prediction and design due to their large size and highly flexible loops in the complementarity-determining regions” (Antibodies: computer-aided prediction of structure and design of function, Microbiol Spectrum, 2014, Pg. 1, Abstract, lines 6-9). Consequently, an antibody’s structure cannot be predicted from function alone accurately i.e. stating the antibody binds ITLN-1 is not a sufficient description.
ITLN-1 antibodies in the prior art are used in immunohistochemistry, not treatment (Yi et al., Intelectin contributes to allergen-induced IL-25, IL-33, and TSLP expression and type 2 response in asthma and atopic dermatitis, Mucosal Immunol, 2017, Pg. 12, ¶ 3, line 4, “immunohistochemistry with rabbit-anti-human intelectin”). There are no known biological inhibitors of ITLN-1.
Gene silencing
Aagaard and Rossi teach “there are a number of hurdles and concerns that must be overcome prior to making [RNA interference] a real therapeutic modality” (RNAi therapeutics: principles, prospects and challenges, Adv Drug Deliv Rev, Pg. 1, Abstract, lines 6-7), wherein gene silencing results from degradation of the mRNA encoding the target protein (Pg. 1, Abstract, lines 5-6, siRNA leads to “degradation of the target mRNA”). “Notably, efficacy… for individual target sites varies widely among siRNA [small interfering RNA]. Important criteria for siRNA efficacy include thermodynamic end stability, target mRNA accessibility, structural features and additional position specific determinants” (Aagaard and Rossi, Pg. 2-3, last ¶ Pg. 2 – first ¶ Pg. 3). In addition, siRNA is known to have off-target gene silencing; however, “predicting off targets the picture is far from complete as a large number of genes with good seed match remain unaffected” (Aagaard and Rossi, Pg. 7, ¶ 1, lines 6-8). These teachings indicate siRNA design is not straightforward.
In the CRISPR-Cas9 system, Roy et al. states guide RNA directs Cas9 to the target DNA site to knockout a gene (CRISPR/Cascade 9-Mediated Genome Editing-Challenges and Opportunities, Front Genet, 2018, Pg. 1, ¶ 2, lines 7-9, “Cascade 9 is a RNA guided dsDNA nuclease… is responsible for cleaving the targeted DNA”; Pg. 2, column 2, ¶ 1, line 4, “Candidate gene knockout” using CRISPR-Cas9); this method introduces insertions or deletions to stop gene expression (Roy et al., Pg. 2, column 1, ¶ 1, line 5, “resulting in deletions or insertions leading to loss of function”). Similar to siRNA, off-target gene silencing is a major challenge in CRISPR-Cas9 “as Cascade 9 may recognize sequences with up to 5 mismatched bases” (Roy et al. Pg. 6, column 2, last ¶, lines 1-3). Therefore, genetic knockdowns via CRISPR-Cas9 are not always effective and predictable.
The term “ITLN-1 inhibitor” encompasses a broad genus because inhibition can occur at the DNA level by reducing transcription of ITLN-1 (Roy et al, Pg. 2, column 1, ¶ 1, line 5, CRISPR-Cas9 system “resulting in deletions or insertions leading to loss of function” of the target gene), at the RNA level by degrading mRNA encoding ITLN-1 (Aagaard and Rossi, Pg. 1, Abstract, lines 5-6, siRNA leads to “degradation of the target mRNA”), or at the protein level by directly binding ITLN-1 to inhibit its activity (Cochran, Pg. R85, column 2, last ¶, line 4, small molecules are selected for “high potency against the target protein”; antagonistic antibodies bind antigens on proteins).
However, Applicant is claiming a large and structurally diverse genus of ITLN-1 inhibitors. Absent empirical determination, one skilled in the art would be unable to immediately envision, recognize, or distinguish at least most of the members comprised within the genus claimed, specifically (i) if the inhibition is done at the DNA, RNA, or protein level and (ii) the identity of the inhibitor.
Mucus-related diseases are diverse and broad, affecting different organs, including but not limited to (i) Sjögren's syndrome in the mouth, (ii) rhinitis in the nose, (iii) COPD, cystic fibrosis (CF), asthma, and bronchitis in the lungs, (iv) ulcers in the stomach, (v) cystic fibrosis in the small intestine, and (vi) Crohn’s disease and ulcerative colitis in the colon (Hansson, Mucus and mucins in diseases of the intestinal and respiratory tracts, J Intern Med, 2019, Pg. 480, Table 1, details examples of mucus-related diseases). Regarding CF in the small intestine, “mucus is accumulating in the distal ileum and typically, these patients require oral laxatives or in severe cases surgery” (Hansson, Pg. 482, column 2, ¶ 2, lines 8-11) to clear the mucus obstruction. In lung disease, “[i]f the mucus is not possible to mobilize and remove by coughing, as in CF and COPD, the attached mucus will remain attached to the epithelium” (Hansson, Pg. 488, column 1, ¶ 3, lines 1-3) i.e. a mucus obstruction forms. These teaching collectively indicate mucus affects an array of organs through different disease pathologies; mucus obstruction is not unique to one disease or organ.
Intelectin-1 is linked to diseases such as Crohn’s disease (Nonnecke et al., Human intelectin-1 [ITLN1] genetic variation and intestinal expression, Sci Rep, 2021, Pg. 1, Abstract, lines 2-3, “GWAS have linked SNPs in ITLN1 [also known as omentin] with susceptibility to Crohn’s disease”) and gastrointestinal and prostate cancer (Paval et al., The Emerging Role of Intelectin-1 in Cancer, Front Oncol, 2022, Pg. 1, ¶ 2, lines 2-3, “patients with gastrointestinal and prostate cancer showed increased concentrations of circulating ITLN1”).
However, disease treatment via ITLN-1 inhibitors is limited. The prior art discloses “Itln knockdown [in an asthmatic mouse model] reduced allergen-induced increases in… development of type 2 response, eosinophilic inflammation, mucus overproduction, and airway hyperresponsiveness” (Pg. 1, Abstract, lines 6-8), wherein the ITLN-1 is shRNA targeting mRNA encoding ITLN-1 (Synbio Technologies, siRNA’s RNA-Interfering Partner: shRNA, 2026, Pg. 2, ¶ 1, lines 8-9, shRNA after processing “binds to the target mRNA in a sequence-specific manner via complementary base pairing” for gene silencing). Here, the shRNA is the ITLN-1 inhibitor. Kerr et al. state “mucus pathology causes mucus plugging” in asthma (Intelectin-1 Is a Prominent Protein Constituent of Pathologic Mucus Associated with Eosinophilic Airway Inflammation in Asthma, American Journal of Respiratory and Critical Care Medicine, 2014, Pg. 1005, column 1, ¶ 3, line 1) wherein “mucus plugs… occlude the airways” (Pg. 1005, column 1, ¶ 3, lines 6-7), indicating a reduction of mucus overproduction also reduces mucus occlusion of airways.
The instant specification discloses ITLN-1 knockdowns in “tracheal airway epithelial basal cells through CRISPR-Cas9 targeting of the ITLN1 gene” (¶ 0076, Example 3) to correlate ITLN-1 expression with mucostasis in the airway, wherein the ITLN-1 inhibitor is the guide RNA and targets the ILTN1 gene at the DNA level (¶ 0057, describes CRISPR guide sequences to silence ITLN1 gene). The instant specification also includes analysis of ITLN-1 eQTL data (¶ 80, Example 5) to correlate ITLN-1 expression with T2 inflammation in asthmatic patients. There is no ITLN-1 inhibitor in this example. The instant specification teaches in vitro experiments or computational analyses; it does not teach a method of reducing mucus obstruction in a subject with an ITLN-1 inhibitor.
As such, claims 1 and 16 are drawn to (i) a method of reducing all mucus obstruction in a subject in need thereof comprising administering to the subject any ITLN-1 inhibitor (claim 1) and (ii) a pharmaceutical composition comprising any ITLN-1 inhibitor for use in reducing all mucus obstruction in a subject in need thereof (claim 16), the full scope of which is not enabled by the method as instantly claimed. It is unclear how all species from the large and broad genus of ITLN-1 inhibitors, incorporated into a method or pharmaceutical composition, could reduce mucus obstruction in a subject.
(3) The relative skill of those in the art and (4) the predictability or unpredictability of the art,
This invention is in a class of invention which the CAFC has characterized as "the unpredictable arts such as chemistry and biology". Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
The use of ITLN-1 inhibitors for reducing mucus obstruction in a subject is not well known by a person having ordinary skill in the art, i.e. someone with a PhD and/or MD (the relative skill of those in the art). The state of the art is limited to shRNA targeting mRNA encoding ITLN-1 in an Itln knockdown in an asthmatic mouse model (Yi et al., see state of the art section for more information). The instant application fails to demonstrate use of ITLN-1 inhibitors in a subject, instead relying on the prior art for support of mucus obstruction reduction in vivo.
The instant application defines ITLN-1 inhibitors by their function rather than structure. This definition encompasses a variety of molecules (e.g. antagonistic antibodies, antagonistic small molecules, and gene silencing via RNA constructs), requiring the person having ordinary skill in the art to determine (i) if the inhibition is done at the DNA, RNA, or protein level and (ii) the identity of the inhibitor. In addition, mucus affects an array of organs through different disease pathologies; mucus obstruction is not unique to one disease or organ (Hansson states mucus obstruction in COPD and cystic fibrosis affects lungs and/or small intestine, see state of the art section for more information). Therefore, the use of any and all species from the large and broad genus of ITLN-1 inhibitors, incorporated into a method or pharmaceutical composition, to reduce all mucus obstruction in a subject within the scope of claims 1 and 16 is not predictable.
The predictability of applying any and all species from the large and broad genus of ITLN-1 inhibitors to reduce all mucus obstruction in a subject would be low given that 1) ITLN-1 inhibitors vary drastically in structure and function (e.g. antagonistic antibodies, antagonistic small molecules, and gene silencing via RNA constructs), 2) a link between ITLN-1 and all mucus overproduction is not established (ITLN-1 associated with asthma as taught by Yi et al. but Hansson teaches mucus obstruction affects a variety of organs, in addition to the lungs, such as the small intestine; see state of the prior art section for more information), and 3) the instant application fails to demonstrate a reduction of all mucus obstruction in a subject with any and all species from the large and broad genus of ITLN-1 inhibitors (the predictability or unpredictability of the art).
(6) The amount of direction or guidance presented, (7) the presence or absence of working examples, and (8) the quantity of the experimentation
The instant specification discloses ITLN-1 knockdowns in “tracheal airway epithelial basal cells through CRISPR-Cas9 targeting of the ITLN1 gene” (¶ 0076, Example 3) to correlate ITLN-1 expression with mucostasis in the airway, wherein the ITLN-1 inhibitor is the guide RNA and targets the ILTN1 gene at the DNA level (¶ 0057, describes CRISPR guide sequences to silence ITLN1 gene). The instant specification also includes analysis of ITLN-1 eQTL data (¶ 80, Example 5) to correlate ITLN-1 expression with T2 inflammation in asthmatic patients. There is no ITLN-1 inhibitor in this example. The instant specification teaches in vitro experiments or computational analyses; it does not teach a method of reducing mucus obstruction in a subject with an ITLN-1 inhibitor. The instant specification does not provide any additional examples or guidance on how to use ITLN-1 inhibitors for reducing mucus obstruction in a subject as recited in claims 1 and 16 (the amount of direction or guidance presented and the presence or absence of working examples).
The prior art discloses “Itln knockdown [in an asthmatic mouse model] reduced allergen-induced increases in… development of type 2 response, eosinophilic inflammation, mucus overproduction, and airway hyperresponsiveness” (Pg. 1, Abstract, lines 6-8), wherein the ITLN-1 is shRNA targeting mRNA encoding ITLN-1 (Synbio Technologies, Pg. 2, ¶ 1, lines 8-9, shRNA after processing “binds to the target mRNA in a sequence-specific manner via complementary base pairing” for gene silencing). Here, the shRNA is the ITLN-1 inhibitor. Kerr et al. state “mucus pathology causes mucus plugging” in asthma (Intelectin-1 Is a Prominent Protein Constituent of Pathologic Mucus Associated with Eosinophilic Airway Inflammation in Asthma, American Journal of Respiratory and Critical Care Medicine, 2014, Pg. 1005, column 1, ¶ 3, line 1) wherein “mucus plugs… occlude the airways” (Pg. 1005, column 1, ¶ 3, lines 6-7), indicating a reduction of mucus overproduction also reduces mucus occlusion of airways.
As such, the instant application is not enabled for the use of any and all species from the large and broad genus of ITLN-1 inhibitors, incorporated into a method or pharmaceutical composition, to reduce all mucus obstruction in a subject delineated in claims 1 and 16.
The instant application defines ITLN-1 inhibitors by their function rather than structure. This definition encompasses a variety of molecules (e.g. antagonistic antibodies, antagonistic small molecules, and gene silencing via RNA constructs). The amount of experimentation would not be reasonable because it would require determining (i) if the inhibition is done at the DNA, RNA, or protein level and (ii) the identity of the ITLN-1 inhibitor for the purposes of reducing mucus obstruction in a subject (see 122[a] rejection for written description for more information). In addition, mucus affects an array of organs through different disease pathologies; mucus obstruction is not unique to one disease or organ (Hansson states mucus obstruction in COPD and cystic fibrosis affects lungs and/or small intestine, see state of the art section for more information). It is not routine to determine how such a broad class of molecules would reduce mucus obstruction in a subject.
Undue experimentation would be required to determine whether the genus of ITLN-1 inhibitors of claims 1 and 16 would reduce mucus obstruction in a subject (the quantity of the experimentation, see MPEP 2164.06).
(5) The breadth of the claims
The scope of claims 1 and 16 is extremely broad; it recites mucus obstruction that is not specific to one disease or organ and the use of a large and diverse genus of ITLN-1 inhibitors that require the specification of the instant application to provide support for the entire scope of the claim. The specification fails to show that a person having ordinary skill in the art could reduce all mucus obstruction without undue experimentation.
The genus of ITLN-1 inhibitors of claims 1 and 16 comprise diverse classes of molecules (e.g. antagonistic antibodies, antagonistic small molecules, and gene silencing via RNA constructs) that require a person having ordinary skill in the art to determine (i) if the inhibition is done at the DNA, RNA, or protein level and (ii) the identity of the ITLN-1 inhibitor (see 122[a] rejection for written description for more information).
It is unclear how the genus of ITLN-1 inhibitors could reduce all mucus obstruction in a subject as recited in claims 1 and 16. Mucus affects an array of organs through different disease pathologies; mucus obstruction is not unique to one disease or organ (Hansson states mucus obstruction in COPD and cystic fibrosis affects lungs and/or small intestine, see state of the art section for more information).
Evidence of efficacy of an ITLN-1 knockdown in an asthmatic mouse model using shRNA is taught by Yi et al in the prior art (see the state of the prior art section for more information). The instant specification teaches in vitro experiments or computational analyses to provide correlative data regarding ITLN-1’s involvement in asthma (¶ 0076, Example 3, ITLN-1 knockdowns in “tracheal airway epithelial basal cells through CRISPR-Cas9 targeting of the ITLN1 gene”;¶ 80, Example 5, ITLN-1 eQTL analysis); it does not teach a method of reducing mucus obstruction in a subject with an ITLN-1 inhibitor. Claims 1 and 16 are directed to complex and unpredictable arts such as chemistry and biology, where the success reduction of a mucus obstruction cannot be readily extrapolated from one disclosed example in the prior art.
Therefore, (i) a method of reducing mucus occlusion of airways due to asthma in a subject in need thereof comprising administering to the subject shRNA (claims 1-8) and (ii) a pharmaceutical composition comprising shRNA for use in reducing mucus occlusion of airways due to asthma in a subject in need thereof (claims 16-20) is supported. Conversely, (i) a method of reducing all mucus obstruction in a subject in need thereof comprising administering to the subject any ITLN-1 inhibitor (claims 1-8) and (ii) a pharmaceutical composition comprising any ITLN-1 inhibitor for use in reducing all mucus obstruction in a subject in need thereof (claims 16-20) is not supported.
Claims 1 and 16 are not enabled because a person having ordinary skill in the art as of the effective filing date of the application would not be able to reduce all mucus obstruction with any and all ITLN-1 inhibitors with a predictability of success for the reasons outlined above. Claims 2-8 and 17-20 are included in this rejection as they incorporate and/or depend on claim 1 or 16.
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 1-20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Yi et al. (Intelectin contributes to allergen-induced IL-25, IL-33, and TSLP expression and type 2 response in asthma and atopic dermatitis, Mucosal Immunol, 2017 Nov;10[6]:1491-1503; IDS filed 12/24/2024, Cite No. 7) as evidenced by Iowa University (Pronuclear Injection Service, 2026), Kerr et al. (Intelectin-1 Is a Prominent Protein Constituent of Pathologic Mucus Associated with Eosinophilic Airway Inflammation in Asthma, American Journal of Respiratory and Critical Care Medicine, 2014 Apr 15, Vol. 189, No. 8, Pg. 1005-1007; IDS filed 12/24/2024, Cite No. 5), Bonser and Erle (Airway Mucus and Asthma: The Role of MUC5AC and MUC5B. J Clin Med. 2017 Nov 29;6[12]:112), and Synbio Technologies (siRNA’s RNA-Interfering Partner: shRNA, 2026).
Regarding claim 1, 6, 14, and 20, Yi et al. teach an “Itln [short hairpin RNA] shRNA transgenic construct” (Pg. 10, ¶ 2, line 13). A transgenic mouse line, also referred to as Itln knockdown mice, was produced by administering the shRNA via “pronuclear microinjection” (Pg. 10, ¶ 2, line 13). “Itln1 expression was mostly suppressed” (Pg. 10, ¶ 2, lines 16-17) in Itln knockdown mice, indicating the shRNA, a biological agent, inhibited ITLN-1 expression. This teaching reads on administering to the subject (mice) an ITLN-1 inhibitor (shRNA) (claim 1), wherein the ITLN-1 inhibitor is a biological inhibitor (claims 6, 14, and 20).
Regarding claims 8-9, Yi et al. do not explicitly state a pharmaceutical composition of shRNA. However, Iowa University states, concerning pronuclear injections in transgenic mice, “the injectionist uses very fine glass microinjection needles to inject picoliters of injection solution into one of the pronuclei” (Pg. 1, ¶ 1, lines 2-4). The pronuclear injection as taught in Yi et al. inherently contains a solution of shRNA as evidenced by the University of Iowa. A solution of shRNA reads on the limitations of an ITLN-1 inhibitor in a pharmaceutical composition (claim 8) and a pharmaceutical composition comprising an ITLN-1 inhibitor (claim 9)
Regarding claims 1, 3, 10-11, 16, and 18, Yi et al. further teach “Itln knockdown [mice] reduced… mucus overproduction” in an asthma model (Pg. 1, Abstract, lines 6-8). Yi et al. do not explicitly state that reducing mucus overproduction also reduces mucus obstruction (claims 1, 10, and 16), specifically mucus plugging (claims 3, 11, and 18). However, Kerr et al. state “mucus pathology causes mucus plugging” in asthma (Pg. 1005, column 1, ¶ 3, line 1; claims 3, 11, and 18) wherein “mucus plugs… occlude the airways” (Pg. 1005, column 1, ¶ 3, lines 6-7; claims 1, 10, and 16), indicating mucus plugging is a form of mucus obstruction and is caused by abnormal mucus production. A reduction of mucus overproduction as taught by Yi et al. inherently is a reduction of mucus obstruction (claims 1, 10, and 16) in the form of mucus plugging (claims 3, 11, and 18) as evidenced by Kerr et al.
Regarding claims 2, 10 and 17, Yi et al. further teach the cytokines “IL-25, IL-33 and TSLP have each been reported to be both necessary and sufficient for type 2 [T2] production… in mouse asthma models” (Pg. 2, ¶ 2, lines 7-8). Exposure to allergens “increased lung IL-25, IL-33 and TSLP protein levels in [wild-type] mice” (Pg. 4, ¶ 4, lines 3-4), indicating the mice had a T2-immune response. As delineated in the 112(b) rejection section, the teaching of a T2-immune response in asthmatic mice reads on the limitation of a T2-high asthmatic subject (claims 2, 10 and 17).
Yi et al. further teach “Itln knockdown reduced allergen-induced… eosinophilic inflammation, mucus overproduction, and airway hyperresponsiveness” in a mouse asthma model (Pg. 1, Abstract, lines 6-8), indicating asthma symptoms in asthmatic mice improved with administration of the ITLN-1 inhibitor (shRNA). Regarding claims 4-5, 12-13, and 19, Yi et al. do not explicitly state the ITLN-1 inhibitor (shRNA) reduces mucus viscosity (claims 4, 12, and 19) nor increases mucociliary clearance (claims 5, 13, and 19). However, Bonser and Erle state “asthmatic sputum is abnormally viscous” (Pg. 8, ¶ 2, line 1; claims 4, 12, and 19) and “prevent[s] mucociliary clearance” (Pg. 8, ¶ 2, line 5; claims 5, 13, and 19), indicating improvement of asthma would be associated with reduced mucus viscosity and increased mucociliary clearance. Alleviation of asthma with the ITLN-1 inhibitor (shRNA) as described in Yi et al. would inherently reduce mucus viscosity (claims 4, 12, and 19) and increase mucociliary clearance (claims 5, 13, and 19) as evidenced by Bonser and Erle.
Regarding claims 7, 15, and 20, Yi et al. do not explicitly state the shRNA is an anti-intelectin molecule. However, Synbio Technologies states shRNAs, after processing to remove its loop sequence, “binds to the target mRNA in a sequence-specific manner via complementary base pairing” (Pg. 2, ¶ 1, lines 8-9) “to achieve gene silencing” (Pg. 1, ¶ 1, line 6). The shRNA used in a genetic knockdown of Itln as taught by Yi et al. inherently binds to the mRNA encoding the protein ITLN-1 as evidenced by Synbio Technologies and reads on the limitation of an anti-intelectin molecule (claims 7, 15, and 20; see 112[b] rejection section for claim interpretation).
Conclusion
Claims 1-20 are pending. Claims 1-20 are rejected. No claims are allowed.
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/J.M.P./Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
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