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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 08/13/2025 has been entered.
Claims 15-17, 20-28 have been amended. Claims 1-2, 4-7, 12-13 have been newly canceled and no claims have been newly added.
Claims 15-17, 20-28, and 34 are currently pending and have been examined on their merits.
Applicant elected the species of Lef-1 signaling with traverse in reply to the restriction requirement on 11/20/2023.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn due to amendment. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
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 15-17, 20-28, and 34 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 inhibiting or treating a degenerative lung disease or disorder in a mammal in need thereof, does not reasonably provide enablement for preventing a degenerative ling disease or disorder.
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 methods of the invention commensurate in scope with these claims.
The claims are drawn to a method of preventing, inhibiting or treating degenerative lung diseases and disorders in a mammal in need thereof comprising administering to the mammal an effective amount of a composition comprising glandular myoepithelial stem cells (MECs) exposed ex vivo to one or modulators of LEF-1 signaling so as to prevent, inhibit or treat the degenerative lung disease or disorder of the mammal.
There are numerous causes for degenerative lung diseases and disorders, including genetic causes such as in cystic fibrosis. Clark et al (US 2014/0336159) disclose that methods of preventing of acute exacerbations of respiratory diseases are a goal of their method (page 4 para 36, para 38, para 40), but do not specifically disclose evidence of prevention of the disease/disorder itself or how prevention of a respiratory disease or disorder is accomplished. When the term “prevent” is used in Clark it appears to be with regard to preventing some symptoms, but not the disease itself.
Duane et al (Am. J. Cell Mol. Biol., 1998) disclose that gene therapy can be used to treat the genetic disease of cystic fibrosis, but do not make any claims that this can prevent this degenerative lung disease (page 750 column 1 to page 751 column 2, page 755 results to page 756, column 2).
Applicant has not provided any evidence that the claimed method would be able to prevent degenerative lung disease and disorders that were caused by any and all situations.
Further, the burden of enabling "prophylaxis" (i.e. prevention), of a disease is greater than that of enabling a treatment method due to the need to screen the subjects susceptible to the respective condition and the difficulty of proof that the administration of the composition was the agent that acted to prevent the condition.
Given that the outcomes of practicing the claimed methods beyond the scope defined above are highly unpredictable, and that the disclosure does not provide sufficient direction, guidance or working examples, the experimentation left to those skilled in the art is extremely extensive. It would initially require experimentation in animal models of the numerous diseases which are within the scope of the claims, using numerous types and subtypes of the cells, under various dosing regimens. The number of possible permutations of these parameters is so large that, even in cases where the requisite methods are routine, the amount of experimentation is beyond the capacity of even the largest research institutions. Since the skilled artisan understands that, for the reasons addressed above, the chances of identifying a set of conditions resulting in a useful outcome are extremely low, the skilled artisan would reasonably view such experimentation as unnecessarily, and improperly, extensive and undue.
Therefore, the currently claimed methods are not fully enabled for their entire scope based on the specification and what is known in the art of preterm birth.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 15-17, 20-21, 24-28 are rejected under 35 U.S.C. 103 as being unpatentable over Clarke et al (US 2014/0336159) in view of Duan et al (Am. J. Cell Mol. Biol. 1998) and Anderson et al (American Journal of Respiratory Cell and Molecular Biology, published January 2017-newly cited).
Regarding claims 15-17, 20 and 26, Clarke disclose methods for treating respiratory diseases with calcium ions (page 1 para 4) wherein the diseases treated include COPD, emphysema, and cystic fibrosis (page 3 para 28). Suitable therapeutic agents may be used in their methods described and that they may be coadministered including anti-inflammatory agents or therapeutics helpful for chronic maintenance of cystic fibrosis (pages 12-13 para 112). Suitable anti-inflammatory agents and/or agents that modulate inflammatory cytokine/chemokine expression or secretion include modulators of Lef1 (page 13 para 121-122).
Clarke does not describe a specific embodiment for treating a respiratory disease, such as cystic fibrosis, with glandular myoepithelial stem cells (MECs) exposed ex vivo to a modulator of Lef1.
Duan teach that there is a need to develop gene therapy strategies in the treatment of cystic fibrosis (page 750 column 1 to page 751 column 2). Lef1 transcription factor expression defines airway progenitor cell targets for in utero gene therapy of submucosal gland in cystic fibrosis (Title, abstract). Duan demonstrate that in vivo targeting to Lef1 transcription factor within airway progenitor cell populations using recombinant retroviral vectors provides stable transgene expression throughout gland morphogenesis and the foundation for the development of gene therapy strategies in the treatment of cystic fibrosis airways (page 751, column 2, second paragraph). Agents that induce expression of Lef1 are described and include Lef1-expressing submucosal gland progenitor cells exposed ex vivo to an activator of Lef1 (page 755 results to page 756, column 2 first paragraph).
Anderson disclose that MECs born early during SMG (airway submucosal glands) morphogenesis are multipotent progenitors with the capacity to differentiate into other glandular cell types (abstract). Anderson also disclose that multipotent stem cells have been shown to exist within SMGs and to contribute to regeneration of the surface airway epithelium following severe injury and are relevant in diseases such as cystic fibrosis (page 3) and that early-born MECs can commit to form multiple cell types during development of airway SMGs (page 13). Anderson also disclose that Lef-1 transcription factor is highly expressed in early SMG progenitors and required for SMG development (page 7).
One of ordinary skill in the art would have been motivated to select cystic fibrosis from the list of respiratory diseases in Clarke and a modulator that induces expression of Lef1 from the list of additional therapeutic agents because Duan teach and suggest that there is a need for treatment strategies for cystic fibrosis and that Lef1 modulators that induce expression of Lef1 are useful in the treatment of this respiratory disease. One of ordinary skill in the art would have been motivated to select MECs as the cell type for exposure to the LEF1 modulator for administration because Anderson teach and suggest that MECs contribute to regeneration of the surface airway epithelium following severe injury, are relevant in diseases such as cystic fibrosis (page 3) and progenitors require Lef-1 expression for SMG development (page 7). One of ordinary skill in the art would have had a reasonable expectation of success because Clarke indicate that cystic fibrosis is a suitable respiratory disease for treatment with their method and Lef1 is a suitable target for modulation and providing an anti-inflammatory effect. One of ordinary skill in the art would have also had a reasonable expectation of success because Clarke, Duan and Anderson are all directed to the treatment of lung diseases/disorders, such as cystic fibrosis, that are connected to Lef-1 expression.
Regarding claim 21, Clarke teach that subjects can be animals or humans (page 6 para 55).
Regarding claims 24-25, Clarke teach wherein the composition is administered intravenously (systemically) or intra-bronchial by inhalation (bronchoscopically) (page 12 para 109).
Regarding claim 27, While Clarke does not specifically describe using an amount that increases the number of ionocytes and/or enhances airway regeneration, Clarke is directed to treating respiratory diseases by attenuation of severity of acute exacerbations (worsening of symptoms) to reduce airway inflammation and excess airway mucus and airflow limitation (page 3 para 28) which would motivate the person of ordinary skill in the art to select amounts that enhance airway regeneration. One of ordinary skill in the art would have had a reasonable expectation of success because Clarke describe optimizing their therapy in combination with other therapeutic agents (page 1 para 4).
Regarding claim 28, Clarke teach wherein the composition for administration may include therapeutic agents such as lithium (page 10 para 85 and 87) or SB-216763 (page 14 para 126).
Therefore, the combined teachings of Clarke et al, Duan et al and Anderson et al render obvious Applicant’s invention as claimed.
Claim(s) 22-23 are rejected under 35 U.S.C. 103 as being unpatentable over Clarke et al (US 2014/0336159) in view of Duan et al (Am. J. Cell Mol. Biol. 1998) and Anderson et al (American Journal of Respiratory Cell and Molecular Biology, published January 2017-newly cited) as applied to claims 15-17, 20-21, 24-28 above, and further in view of Cypel et al (WWW. SciencetranslationMedicine.org, 2009).
Regarding claims 22-23, Clarke does not specifically describe combining their treatment with a lung transplant, but they do disclose wherein their calcium-containing compositions increased airway surface lining height in cells obtained from excess tissue from donor lungs and excised recipient lungs that were obtained at the time of lung transplant. These data show that their formulations are effective in increasing ASL height in CF patient lung cells (page 30 Example 2 para 265-270).
Cypel teach that lung transplant is a lifesaving therapy for patients suffering from end-stage lung diseases, such as emphysema and cystic fibrosis. Cypel describe a strategy to preserve lungs with gene therapy (abstract, page 1).
One of ordinary skill in the art would have been motivated to combine the Clarke method of treating cystic fibrosis with Lef1 gene therapy as modified by Duan and Anderson above for before, during or after a lung transplant because Cypel teach that lung transplant is a lifesaving therapy for patients suffering from end-stage lung diseases, such as emphysema and cystic fibrosis, and that it can be combined with gene therapy to enhance the therapeutic effect. One of ordinary skill in the art would have had a reasonable expectation of success because Clarke teach that their composition was effective when exposed to airway cells obtained during a lung transplant.
In addition, it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third option to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art. In re Kerkhoven (MPEP 2144.06).
Therefore, the combined teachings of Clarke et al, Duan et al, Anderson et al and Cypel et al render obvious Applicant’s invention as claimed.
Claim(s) 34 is rejected under 35 U.S.C. 103 as being unpatentable over Clarke et al (US 2014/0336159) in view of Duan et al (Am. J. Cell Mol. Biol. 1998), Anderson et al (American Journal of Respiratory Cell and Molecular Biology, published January 2017-newly cited) and Cypel et al (WWW. SciencetranslationMedicine.org, 2009) as applied to claims 15-17, 20-28 above, and further in view of Nagai et al (Gene Therapy 2014).
Regarding claim 34, Clarke does not specifically describe combining their treatment with valproic acid. However, Clarke do describe optimizing their therapy in combination with other therapeutic agents (page 1 para 4) including gene therapy (page 13 para 122 and page 17 para 149).
Nagai teach that valproic acid is a clinically safe compound that is useful in the treatment of cystic fibrosis, both on its own as a reducer of inflammation and also when used in conjunction with gene therapy as it enhanced vector-mediate gene expression (page 2 second paragraph, page 3).
One of ordinary skill in the art would have been motivated to additionally include in the Clarke method of treating cystic fibrosis with Lef1 modulation as modified by Duan and Anderson above to further include valproic acid because Nagai teach that valproic acid is a clinically safe compound that is useful in the treatment of cystic fibrosis, both on its own as a reducer of inflammation and also when used in conjunction with gene therapy as it enhanced vector-mediate gene expression (page 2 second paragraph, page 3). One of ordinary skill in the art would have had a reasonable expectation of success because Clarke describe optimizing their therapy in combination with other therapeutic agents, including gene therapy and Nagai indicate that valproic acid has been proven to be clinically safe and useful in the treatment of cystic fibrosis.
In addition, it is prima facie obvious to combine compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third option to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art. In re Kerkhoven (MPEP 2144.06).
Therefore, the combined teachings of Clarke et al, Duan et al, Anderson et al, Cypel et al and Nagai et al render obvious Applicant’s invention as claimed.
Response to Arguments
Applicant's arguments filed 08/13/2025 have been fully considered but they are not persuasive.
Applicant argues that their amendments to the claims obviate the previous rejection under 35 USC 112b and requests withdrawal of this rejection.
This is found persuasive and the rejection under 35 USC 112(b) has been withdrawn.
Applicant argues that there is nothing in the Clarke and Duan references that suggest the currently amended method claims either separately or combined that includes MECs as claimed.
This is not found persuasive because the previous rejection has been replaced with a new rejection cited above that now includes the teaching of the Anderson reference.
In addition, in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
In this case, Clarke do describe optimizing their therapy in combination with other therapeutic agents (page 1 para 4) including gene therapy (page 13 para 122 and page 17 para 149).
Applicant argues that combining separate items from long lists, without any pointer in the references toward that specific combination, is impermissible hindsight reconstruction.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Clarke do describe optimizing their therapy in combination with other therapeutic agents (page 1 para 4) including gene therapy (page 13 para 122 and page 17 para 149). Duan and Anderson describe ways in which treatment of lung diseases, such as cystic fibrosis, can be addressed and improved.
In addition, it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third option to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art. In re Kerkhoven (MPEP 2144.06).
Applicant argues that Cypel and Nagai do not remedy the defects of Clarke and Duan.
This is not found persuasive because the current rejection relying on Clarke, Duan and Anderson is not deemed to be defective.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAURA J SCHUBERG whose telephone number is (571)272-3347. The examiner can normally be reached 8:30-5:00 EST.
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LAURA J. SCHUBERG
Primary Examiner
Art Unit 1631
/LAURA SCHUBERG/Primary Examiner, Art Unit 1631
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