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 .
Claims status
Applicants reply filed 12/11/2025 is acknowledged.
Claims 35-38, 40 is/are cancelled and claims 49-60 is/are newly added.
Claims 43, 44, 48 were previously withdrawn since they depended from withdrawn claims. However these claims are now amended to depend from claim 33, which was elected in the response filed 4/14/2025.
Claims 1-3, 6-9, 11, 12, 17-19, 33, 41, 43-60 is/are currently pending with claims 1-3, 6-9, 11, 12, 17-19, 45, 46 is/are withdrawn. Claims 33, 41, 43, 44, 47-60 is/are under examination.
Claim Objections - New, necessitated by claim amendments
Previous Objection to Claim 33 is withdrawn in light of claim amendment.
Claim 33 objected to because of the following informalities: Claim recites “knocking out Cdc42 genes” in line 4. Use of singular version of “genes” is recommended.
Claim 41 objected to because of the following informalities: Claim recites “knocking out Cdc42 genes” in line 4. Use of singular version of “genes” is recommended.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b) - New, necessitated by claim amendments
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.
Previous rejections of Claims 33, 35-38, 40, 41 and 47 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention are withdrawn in light of claim amendments. However, amendment to claims introduce substantial new indefinites issues.
Claims 33, 41, 43, 44, 47-60 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.
Claim 33 is directed to method for screening candidate drugs from treating pulmonary fibrosis by applying the candidate drugs to a mouse model which is constructed by “knocking-out Cdc42 genes in the AT2 cells and subsequently increasing mechanical tension”. It is unclear if the method requires the application of mechanical tension to the Cdc42 knockout mouse during the screening method or if it is sufficient that mechanical tension is applied to the Cdc42 knockout mouse prior to its use in the instant screening method.
Claim 41 is directed to method for evaluation of therapeutic effects of a candidate drug for pulmonary fibrosis by applying the candidate drug to a mouse model which is constructed by “knocking-out Cdc42 genes in the AT2 cells and subsequently increasing mechanical tension”. It is unclear if the method requires the application of mechanical tension to the Cdc42 knockout mouse during the evaluation method or if it is sufficient that mechanical tension is applied to the Cdc42 knockout mouse prior to its use in the instant evaluation method.
Claim 43 recites “wherein the mouse model is detected by using a pair of primers”. It is unclear what is meant by detecting a mouse by using primers, thus it is unclear in what way are the primers being used in this claim. For the purpose of compact prosecution, the claim(s) 43 is/are interpreted as “wherein the Cdc42 gene knockout in the mouse model is detected by using a pair of primers”.
Claim 48 recites “wherein the step of knocking-out Cdc42 gene in AT2 cells in a PNX-treated animal comprises knocking out Cdc42 specifically in lung AT2 cells by using a Spc-CreER allele”. There is insufficient antecedent basis for a “step of knocking-out Cdc42 gene in AT2 cells in a PNX-treated animal”. No such step is recited in claim 33. Although the method of claim 33 uses an animal constructed by knocking out Cdc42 gene in AT2 cells, this is not an active step in claim 33. Furthermore, claim 33 has no recitation of “PNX-treated animal. For the purpose of compact prosecution, the claim(s) 48 is/are interpreted as “wherein the mouse model of pulmonary fibrosis constructed by knocking out Cdc42 gene in AT2 cells and mechanical tension is increased by PNX.”
Claim 53 recites “wherein the step of knocking-out Cdc42 gene in AT2 cells in a PNX-treated animal comprises knocking out Cdc42 specifically in lung AT2 cells by using a Spc-CreER allele”. There is insufficient antecedent basis for a “step of knocking-out Cdc42 gene in AT2 cells in a PNX-treated animal”. No such step is recited in claim 41. Although the method of claim 41 uses an animal constructed by knocking out Cdc42 gene in AT2 cells, this is not an active step in claim 41. Furthermore, claim 41 has no recitation of “PNX-treated animal. For the purpose of compact prosecution, the claim(s) 53 is/are interpreted as “wherein the mouse model of pulmonary fibrosis constructed by knocking out Cdc42 gene in AT2 cells and mechanical tension is increased by PNX.”
Claim 58 recites “wherein the mouse model is detected by using a pair of primers”. It is unclear what is meant by detecting a mouse by using primers, thus it is unclear in what way are the primers being used in this claim. For the purpose of compact prosecution, the claim(s) 43 is/are interpreted as “wherein the Cdc42 gene knockout in the mouse model is detected by using a pair of primers”.
Claims 43, 44, 47-52 is/are rejected due their dependence on claim 33 because they do not clarify the 112b issue noted with claim 33.
Claims 53-60 is/are rejected due their dependence on claim 41 because they do not clarify the 112b issue noted with claim 41.
Claim 44 is/are rejected due their dependence on claim 43 because they do not clarify the 112b issue noted with claim 43.
Claim 59 is/are rejected due their dependence on claim 58 because they do not clarify the 112b issue noted with claim 58.
Claim Rejections - 35 USC § 101 - Withdrawn
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Rejection of Claims 33, 35-38, 40, 41 and 47 under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter is withdrawn in light of claim amendment. Claims are amended to recite a method with active method steps.
Rejection of Claim 41 under 35 U.S.C. 101 because the claimed invention is directed to abstract idea without significantly more is withdrawn in light of claim amendment. Claims are amended to remove recitation of the abstract idea.
Claim Rejections - 35 USC § 112(a) – New “New Matter” rejection; Written Description and Enablement rejections maintained in part; Updated for new claims
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.
New Matter
Claims 33, 41, 43, 44, 47-60 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. 37 CFR 1.118 (a) states that “No amendment shall introduce new matter into the disclosure of an application after the filing date of the application”.
Claims 33 and 41 are directed to methods for screening or evaluating candidate drugs for treatment of pulmonary fibrosis. These have been amended to recite steps of (a) applying candidate drugs to a mouse model of pulmonary fibrosis and then in step (b) measuring specifically recited pulmonary fibrosis indicators such as weight loss, respiration rate, collagen deposition, fibrotic lesions and expression levels of TGFb/SMAD. Claim 33 is amended to recite a step (c) wherein the candidate drug is selected based on the measurement results in step (b). Claim 41 is amended to recite a step (c) wherein the therapeutic effect of the candidate drug is ascertained based on the measurement results in step (b) in comparison to a “control mouse model which is not applied with the candidate drug”
The originally filed specification does not disclose such methods. The originally filed specification does not explicitly or implicitly disclose methods for screening or evaluating drug candidates wherein the specifically recited pulmonary fibrosis indicators are measured. Furthermore, the originally filed specification does not explicitly or implicitly disclose methods wherein a selection or evaluation of a candidate drug is made based on these specifically recited pulmonary fibrosis indicators. Additionally, no comparison of a candidate drug with a control mouse is disclosed.
Applicant indicates that at least paras [0126], [0127], [0133] and [0140] in the specification provide support for this newly added limitation. These paragraphs are referencing the associated PGPUB (US 2022/0273822 A1). Paras [0126] and [0127] disclose the mouse model with the Cdc42 knockout with PNX wherein the mice showed weight loss and increased respiration rate after PNX. Para [0133] discloses that fibrotic foci are markers of pulmonary fibrosis, and that in the mouse model with the Cdc42 knockout after PNX fibrotic foci appear. Para [140] is the heading for example 9. In this example, the mouse model with the Cdc42 knockout after PNX had an increase in TGFb/SMAD signaling. A double knockout mouse model was created with TGFb and Cdc42 knockouts.
These paras are directed to example describing the phenotype of the mouse model recited in the claims when subjected to PNX. These are not directed to a method for screening or evaluating a drug candidate. No candidate drug was applied and there is no disclosure that in a method for screening or evaluating a drug candidate, weight loss, respiration rate, collagen deposition, fibrotic lesions and expression levels of TGFb/SMAD are to be measured and based on these measures a drug candidate is selected. Neither these nor any other paragraphs in the specification explicitly or implicitly provide support for such steps as amended into claims 33 and 41.
MPEP 2163.06 notes “If new matter is added to the claims, the examiner should reject the claims under 35 U.S.C. 112, first paragraph - written description requirement. In re Rasmussen, 650 F.2d 1212, 211 USPQ 323 (CCPA 1981).” MPEP 2163.02 teaches that “Whenever the issue arises, the fundamental factual inquiry is whether a claim defines an invention that is clearly conveyed to those skilled in the art at the time the application was filed...If a claim is amended to include subject matter, limitations, or terminology not present in the application as filed, involving a departure from, addition to, or deletion from the disclosure of the application as filed, the examiner should conclude that the claimed subject matter is not described in that application. MPEP 2163.07 provides specific examples of amendments that are supported by original disclosure: Rephrasing, Obvious Errors, Inherent Function/Theory/Advantage.
Thus, newly added step (b) and (c) to claims 33 and 41 are deemed new matter.
Written Description
Rejection of Claims 35-38, 40 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 is moot due to claim cancellation.
Claims 33, 41, 47 remain and claims 43, 44, 48-60 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.
In making a determination of whether the application complies with the written description requirement under 35 U.S.C. 112(a) or 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant is claiming and what Applicant has possession of.
As noted above in the U.S.C. 112b rejection, the claims are indefinite, vague and unclear. Yet, the Office has made every attempt to construe the claims in what the Office believes is the intent of the Applicants in the interest of compact prosecution.
The following claim limitations lack written description:
“increasing mechanical tension” in alveolar epithelium in vivo by any means as broadly claimed.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V, v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.
Regarding mechanical tension, no specific definition is provided. Furthermore, no guidance pertaining to how much tension is sufficient to generate the claimed animal model is provided. As such, any means for increasing mechanical tension in vivo that increases tension by any amount on the alveolar epithelium, that includes AT2 cells, is embraced. For example, hyperventilation that increases mechanical stretch on the lungs is embraced. However, only two means of increasing mechanical tension in vivo are disclosed: pneumonectomy (PNX), a surgical means, that produces temporary increase in mechanical tension and knockout of Cdc42 gene in AT2 cells of mice that produces an increase in mechanical tension in an age-dependent manner. In [012], the specification states “Preferably, the step of increasing the mechanical tension on alveolar type II (AT2) cells involves the step of deactivating Cdc42 in AT2 cells (Cdc42 AT2 null)”. In [0137], the specification states “The loss of alveoli resulting from PNX substantially increases mechanical tension exerted upon the alveolar epithelium. The subsequent efficient regeneration of alveoli that occurs in normal mice eventually reduces the intensity of the mechanical tension to pre-PNX levels; however, as Cdc42 null AT2 cells are unable to differentiate into AT1 cells and thus cannot regenerate new alveoli (Figures 3A and 3B), the alveolar epithelium of Cdc42 AT2 null mice continue to experience elevated mechanical tension, which results in the progressive development of fibrosis (Figure 4)”. In [0130], the specification states “We found no significant fibrotic changes before the Cdc42 AT2 null mice reached 10-months of age (Figure 5C). It is also observed that by 12 months, fibrosis has obviously begun to develop in the subpleural regions of Cdc42 AT2 null lungs and to progress toward the center of the lung after 12 months (Figure 5C).”
Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was “ready for patenting” such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaff v. Wells Eiees., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641,1647 (1998); Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm., 927 F. 2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991).
In the instant case, only PNX-induced and/or AT2-knockout of Cdc42-induced mechanical tension is described and reduced to practice. No distinguishing identifying characteristics of the mechanical tension required for the animal model have been disclosed. Furthermore, even PNX or AT2-knockout of Cdc42 as a means for mechanical tension is not characterized – such as no description of amount, type and duration of mechanical tension produced by PNX on alveolar epithelium is provided. A skilled artisan is unable to envision other mechanical means of inducing alveolar tension that would result in the claimed model. The claims require essential or critical elements which are not adequately described in the specification, and are not conventional in the art before the effective filing date. Therefore, the limitations pertaining to increasing mechanical tension on alveolar epithelium/AT2 cells in vivo is not adequately described and lacks written description.
Scope of Enablement
Rejection of Claims 35-38, 40 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the scope of enablement requirement is moot due to claim cancellation.
Claims 33, 41, 47 remain and claims 43, 44, 48-60 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 a method using a mouse model of pulmonary fibrosis which comprises a Ccd42 gene knockout in AT2 cells and subsequently increasing mechanical tension on the alveolar epithelium by aging and/or PNX,
does not reasonably provide enablement for a method wherein the mechanical tension on the alveolar epithelium is increased by any means other than PNX or aging.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.” See MPEP § 2164. These factors include, but are not limited to: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The office has analyzed the specification in direct accordance to the factors outlines in In re Wands. MPEP 2164.04 states: “[W]hile the analysis and conclusion of a lack of enablement are based on factors discussed in MPEP 2164.01(a) and the evidence as whole, it is not necessary to discuss each factor in written enablement rejection.” These factors will be analyzed, in turn, to demonstrate that one of ordinary skill in the art would have had to perform “undue experimentation” to make and/or use the invention and therefore, applicant’s claims are not enabled.
(A) With respect to the breadth of the claims: the claims as currently drafted encompass a Cdc42 gene knockout mouse subjected to increase in mechanical tension on the alveolar epithelium by any means. Consequently, the breadth of the claims is broad.
(B), (F), (G) The nature of the invention, the amount of direction and working examples provided by the applicant: The invention is in the field of mouse models of pulmonary diseases such as pulmonary fibrosis. The specification discloses that PNX induced lung injury results in an temporary increase in mechanical tension on the alveolar epithelium [0137]. Furthermore, the specification discloses that loss of Cdc42 function in AT2 cells also results in increased mechanical tension in a delayed, age-dependent manner ([012], Example 5). To generate the mouse model comprising loss of Cdc42 function in AT2 cells, the specification uses a AT2-cell specific promoter driving the Cre-Lox system (Figure 2). The specification discloses a mouse model comprising both PNX and loss of Cdc42 function in AT2 cells (Example 3).
The applicants have not provided working examples wherein mechanical tension in the alveolar epithelium is increased by any means other than PNX and/or aging of Cdc42 knockout mouse.
As noted in the written description rejection, the applicants have not provided any guidance pertaining to the requisite type, amount and duration of mechanical tension sufficient for the claimed model of pulmonary fibrosis.
(C), (D), (E) With respect to the state of the prior art, the level of one of ordinary skill and predictability of the art: Role of AT2 cells in pulmonary fibrosis, especially idiopathic pulmonary fibrosis, is well accepted in the art. Parimon et al (Int. J. Mol. Sci. 2020, 21, 2269), a post-filing review of the literature, states that “Early theories that chronic inflammation and repetitive damage to the alveolar epithelium promotes fibrogenesis and scar formation in the pathogenesis of lung fibrosis [18] have been largely rejected due to the lack of ongoing inflammation in IPF and the general ineffectiveness of immunosuppressive medications in curbing disease progression. In contrast, a preponderance of more recent evidence suggests that the alveolar epithelium plays a central role. Indeed, honeycombed regions of the lungs have discontinuous epithelium adjacent to hyperplastic alveolar epithelial type II cells (AT2) [19]. Accordingly, the more contemporary paradigm is that chronic injury to distal lung tissue leads to either loss or altered function of epithelial stem cells (i.e., AT2 cells), that promote dysregulated repair and pathogenic activation of fibroblasts” (Introduction, para 2). Selman et al (Respir Res 2002, 3:3; cited in IDS 4/20/2022), a review of IPF literature prior to 2002, had noted that “In general terms, it seems that in IPF/UIP, the ability of type 2 alveolar cells to restore damaged type 1 cells is seriously affected [15]. Importantly, altered alveolar type 2 cells synthesize a variety of enzymes, such as matrix metalloproteinases, cytokines and growth factors, suggesting that the contribution of the epithelium in the extracellular matrix remodeling is greater than commonly thought. In fact, during the development of IPF, alveolar epithelial cells appear to be responsible for the expression and release of most, if not all, the profibrotic cytokines and growth factors that have usually been associated with inflammatory cells, primarily alveolar macrophages. Thus, for example, Kapanci et al. [16] examined lung biopsy specimens from a number of IPF patients and demonstrated that type 2 alveolar epithelial cells constitute the main site of synthesis of transforming growth factor (TGF)-β1 and tumor necrosis factor-α. They also seemed to be closely related to the presence of myofibroblastic foci. Similar results were obtained by Nash et al. [17],” (see section : The alveolar epithelial cell connection on page 3).Sisson et al (Am J Respir Crit Care Med Vol 181. pp 254–263, 2010; cited in IDS 1/30/2023) showed that transgenic mice with AT2 cell specific expression of diptheria toxin receptor that result in decrease in AT2 cells causes lung fibrosis (Abstract). Liu et al (Cell Reports 16, 1810–1819, August 16, 2016; cited in IDS 12/4/2024) disclosed the claimed mouse model with loss of Cdc42 function in AT2 cells specifically and this model results in reduced AT2 proliferation and increased mechanical tension (Graphical abstract, Figure 4). Liu also disclose PNX as a means for increasing mechanical tension in mice.
Taken together, PNX and reduced proliferation of AT2 cells, such as by Cdc42 knockout, are known to result in increased mechanical tension on the alveolar epithelium overtime. However, the art pertaining to any other means to increase mechanical tension or physical means of mechanical tension that result in IPF is lacking.
(H) Undue experimentation would be required to practice the invention as claimed due to the amount of experimentation necessary to identify the broadly claimed means for increasing mechanical tension in alveolar epithelium that result in PF/IPF. The specification provides no guidance regarding the features of the mechanical tension, such as type, intensity and duration that resulted in IPF. The limited amount of guidance in the form of varied working examples in the specification and the state of the prior art and its unpredictability combined with the broad breadth of the claims result in the claims being enabled for a scope far smaller than currently embraced by the claims.
MPEP §2164.01(a), 4th paragraph, provides that, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1157, 1562; 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
Genentech Inc. v. Novo Nordisk A/S, 42 USPQ2d 1001, 1005 (CA FC), states that, “[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable,” citing Brenner v. Manson, 383 U.S. 519, 536 (1966) (stating, in the context of the utility requirement, that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion”). The Genentech decision continued, “tossing out the mere germ of an idea does not constitute enabling disclosure. While every aspect of a generic claim certainly need not have been carried out by an inventor, or exemplified in the specification, reasonable detail must be provided in order to enable members of the public to understand and carry out the invention.” Id. at p. 1005.
After applying the Wands factors and analysis to claims 33, 41, 43, 44, 47-60 in view of the applicant’s entire disclosure, and considering the In re Wright, In re Fisher and Genentech decisions discussed above, it is concluded that the practice of the invention as claimed would not be enabled by the written disclosure. Therefore, claim 33, 41, 43, 44, 47-60 are rejected under 35 U.S.C. §112(a) for failing to disclose sufficient information to enable a person of skill in the art to make and use the claimed invention to its full scope.
Claim Rejections - 35 USC § 102 - Withdrawn
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.
Rejection of Claim(s) 33, 35-38, 47 under 35 U.S.C. 102(a)(1) as being anticipated by Heise et. Al. (JBC, Vol. 286, No. 20, May 2011; cited in IDS 12/4/2024) is withdrawn because Heise does not teach an animal model with a Cdc42 gene knockout.
Rejection of Claim(s) 33, 35-38, 40, 41, 47 under 35 U.S.C. 102(a)(1) as anticipated by Liu et al (Cell Reports 16, 1810–1819, August 16, 2016; cited in IDS 12/4/2024) as evidenced by Sisson et al (Am J Respir Crit Care Med Vol 181. pp 254–263, 2010; cited in IDS 1/30/2023) ) is withdrawn because Liu does not teach pulmonary fibrosis.
Claim Interpretation
Claim 33 is directed to a method for screening candidate drugs and claim 41 is directed to a method of evaluating the therapeutic effects of a candidate drug. In both these claims, the candidate drug is applied to a mouse model of pulmonary fibrosis. The claims recite product-by-process limitations regarding the mouse model of pulmonary fibrosis (see use of phrase “constructed by”). According to MPEP 2113, “Product-by-process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps.” The process steps of “constructed by knocking-out Cdc42 genes in AT2 cells and subsequently increasing mechanical tension on alveolar epithelium of the mouse model” impart the following structure to the claimed mouse model of pulmonary fibrosis: the mouse comprises a Cdc42 knockout at least in the AT2 cells and is subjected to an increase in mechanical tension on alveolar epithelium at some point after the knockout.
Claim 43, 44 and claims 58, 59, in view of 112b interpretation presented above, recite means for detecting Cdc42 knockout in the mouse model. These claims do not recite an active method step or provide additional meaning, purpose or structure to the active steps of claims 33, 41 (See MPEP 2111.04(I)). A means for detecting Cdc42 knockout, such as by using primers, does not limit the mouse model recited in the active steps of claims 33 or 41. Therefore, prior art(s) that anticipates and/or renders obvious a mouse model comprising Cdc42 knockout at least in AT2 cells meets the claim limitations of claims 43, 44, 58, 59.
Claim 50 recites “wherein the mouse model shows progressive lung fibrosis phenotype after” PNX. This is not an active method step or provide any additional structure to the mouse model of claim 49 which already comprises a Cdc42 gene knockout with PNX. The feature recited in claim 50 is inherent to a Cdc42 gene knockout mouse especially when combined with PNX. Therefore, prior art(s) that anticipates and/or renders obvious a mouse model comprising Cdc42 knockout at least in AT2 cells, especially along with PNX, meets the claim limitations of claims 50.
Similar interpretation is applicable to claim 55, that depends from independent claim 41.
Claim 51 recites “wherein the mouse model without undergoing PNX shows progressive lung fibrosis phenotype in middle age and old age”. Claim 52 recites “wherein the mouse model without undergoing PNX shows progressive lung fibrosis phenotype in middle age and old age”. Similar to claim 50, these claims do not recite an active method step or provide any additional structure to the mouse model of claim 33 which already comprises a Cdc42 gene knockout. The feature recited in claims 51 and 52 are inherent to a Cdc42 gene knockout mouse. Therefore, prior art(s) that anticipates and/or renders obvious a mouse model comprising Cdc42 knockout at least in AT2 cells meets the claim limitations of claims 51 and 52.
Similar interpretation is applicable to claims 56, 57, that depend from independent claim 41.
Claim Rejections - 35 USC § 103 - New, necessitated by claim amendments
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) 33, 41, 43, 44, 47-60 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lv et al (PLoS ONE 8(7): e68631. doi:10.1371/journal.pone.0068631) and Liu et al (Cell Reports 16, 1810–1819, August 16, 2016; ref of record) in view of Sisson et al (Am J Respir Crit Care Med Vol 181. pp 254–263, 2010; ref of record).
Regarding claims 33 and 41, Lv teaches method for screening candidate drug and evaluating its therapeutic efficacy by applying the candidate drug to a mouse model of pulmonary fibrosis (=step a), measuring collagen I deposition, fibrotic lesions, and expression levels of TGF3 and/or SMAD as indicators of pulmonary fibrosis after drug application (=step b) and thus selecting the candidate based on the measurement in step b (=step c of claim 33) in comparison to a control group to which the drug was not applied (=step c of claim 41) (Materials and Methods: Generation of pulmonary fibrosis and therapeutic protocol, Morphological evaluation of lung sections; Figure 1, 2, S1A, S2A).
Lv uses bleomycin and silica induced pulmonary fibrosis.
Lv does not use a mouse model of pulmonary fibrosis wherein the mouse comprises a Cdc42 knockout in AT2 cells followed by increase in mechanical tension on alveolar epithelium.
Liu teaches a mouse model comprising Cdc42 knockout in AT2 cells followed by increase in mechanical tension on alveolar epithelium by PNX treatment (Figure 4C; as required by claim 49 and 54). Liu generates the AT2 cell specific Cdc42 knockout by Spc-Cre, which is a AT2 cell specific promoter driving Cre expression (Figure 4C; as required by claim 48 and 53). Liu teaches that their mouse model has reduced AT2 proliferation (Figure 4G). Liu also discloses that the knockout of downstream effector of Cdc42 (i.e. Yap) results in reduction in AT1 cells and reduction in differentiation of AT2 cells into AT1 cells (Figure 1H-K).
Regarding claims 43, 44, 58 and 59, based on the claim interpretation above, since Liu teaches the mouse model with the structure of the mouse model of claim 33 and 41, Liu’s model can be inherently detected on the basis of SEQ ID NO: 4 using primers SQ ID NO: 1 and 2.
Regarding claims 50, 55, based on the claim interpretation above, since Liu teaches the mouse model with the structure of the mouse model of claim 49 and 54, Liu mouse model inherently shows progressive lung fibrosis after PNX.
Regarding claims 51, 52, 56 and 57, based on the claim interpretation above, since Liu teaches the mouse model with the structure of the mouse model of claim 33 and 41, Liu mouse model inherently shows age-dependent lung fibrosis in middle and old age, including 12 months of age, without PNX.
Therefore, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to substitute the mouse model of Lv with mouse model of Liu to in Lv’s method for screening candidate drug for pulmonary fibrosis. An ordinary artisan is motivated to make such a substitution because an ordinary artisan is motivated to test candidate drugs in more than one model for a disease. An ordinary artisan would reasonably expect to substitute the mouse model of Lv with mouse model of Liu in a method for screening candidate drug for pulmonary fibrosis because Liu teaches that their mouse model that comprises AT2-specific Cdc42 knockout and PNX induced mechanical tension results in reduction in AT2 proliferation and knockout of downstream effector of Cdc42 (i.e. Yap) results in reduction in AT1 cells and reduction in differentiation of AT2 cells into AT1 cells. This is because an ordinary artisan was aware of the role of AT2, reduction in AT2 proliferation and resultant reduction in AT1 in pulmonary fibrosis, including idiopathic pulmonary fibrosis. For example, Sisson teaches that idiopathic pulmonary fibrosis results from “type II alveolar epithelial cells fail to repair the damaged epithelium as a result of ineffectual proliferation, migration, and/or differentiation, and this leads to interstitial scarring (1).” (page 254, col. 1, para 2). Sisson also developed a mouse model for idiopathic pulmonary fibrosis by specifically targeting AT2 in vivo using diphtheria toxin that results in AT2 cell death (Generation of Transgenic Mice; Figure 8). Sisson conclude that “Our findings provide direct evidence specifically linking the targeting of type II cells for injury to the development of lung fibrosis” (Discussion, last para). Therefore, an ordinary artisan reasonably expects Liu’s mouse model to recapitulate some aspect of pulmonary fibrosis, including idiopathic pulmonary fibrosis and thus have utility in methods for screening drug candidates for pulmonary fibrosis, including idiopathic pulmonary fibrosis (as required by claims 47, 60).
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in
the art at the effective time of filing of the invention, especially in the absence of evidence to the
contrary.
Response to Arguments
Applicant's arguments filed 12/11/2025 regarding the U.S.C. 112a written description and scope of enablement rejection have been fully considered and persuasive in part due to claim amendments. However, arguments regarding means for increasing mechanical tension were not persuasive and thus rejections are maintained in part.
Applicant argue that “Regarding mechanical tension, as known by one skilled in the art, the mechanical tension on alveolar epithelium can be increased due to lobar lung expansion (e.g. PNX treatment) or aging of the mouse ( e.g. at 12 month of age or older).” (page 10, para 4). Applicant point to examples in the specification that disclose increasing mechanical tension by PNX or aging (page 10, paras 5, 6).
This is not persuasive because the rejection already acknowledges that the specification disclose increasing mechanical tension by PNX or aging. However the scope of the claim is broader i.e. it embraces inducing mechanical tension means by any means to any extent and still results in the claimed mouse model. The specification does not provide sufficient disclosure to embrace this broad genus. No distinguishing identifying characteristics of the mechanical tension required for the animal model have been disclosed. Furthermore, even PNX or AT2-knockout of Cdc42 as a means for mechanical tension is not characterized – such as no description of amount, type and duration of mechanical tension produced by PNX on alveolar epithelium is provided. A skilled artisan is unable to envision other mechanical means of inducing alveolar tension that would result in the claimed model. Undue experimentation would be required due to this breadth of the claim and lack of predictability with regards how much and what type of mechanical tension would result in a mouse model for pulmonary fibrosis.
Applicant’s arguments with respect to the U.S.C. 102 rejection of claim(s) 33, 35-38, 40, 41, and 47 in view of Liu have been considered but are moot because the new ground of rejection necessitated by claim amendments.
Arguments pertinent to instant U.S.C. 103 rejection of claim(s) in view of Lv, Liu and Sisson are addressed below.
Applicant argue that results from Liu “cannot necessarily lead to pulmonary fibrosis” because AT2 dysfunction does not “exclusively lead to fibrosis” (page 15, para 1). Based on this Applicant contend that a skilled artisan would not analyze Liu’s mouse model for pulmonary fibrosis.
In response, Applicant appear to agree that AT2 dysfunction does lead to fibrosis. Exclusivity is not a requirement for animal models, especially for diseases like idiopathic pulmonary fibrosis with no clear cause. Sisson clearly identifies the role of AT2 in idiopathic pulmonary fibrosis and this is sufficiently motivating to an ordinary artisan to use a model that targets AT2 to screen drug targets such as AT2 or AT1 protecting drugs to treat idiopathic pulmonary fibrosis.
Applicant also note that “Liu is also made by the inventors of this application” and in Liu samples were collected at 5 or 14 days after PNX and long term observation was not performed (page 15, para 2). Applicant assert that no pulmonary fibrosis phenotype was observed by the naked eye at the time point tested in Liu (page 15, para 3). Applicant also allege that “the inventors discovered by chance that Cdc42 AT2 null mice exhibited pulmonary fibrosis” (page 16, para 1).
This is not persuasive because the claim does not require any specific duration of exposure. Observation of pulmonary fibrosis phenotype by the naked eye is also not a requirement. An ordinary artisan would not merely use naked eye observations for pulmonary fibrosis. Additionally, as noted above and implicitly agreed by the Applicant, relation between AT2 dysfunction and pulmonary fibrosis was known. Thus, further exploration of Liu’s mouse that has AT2 dysfunction to reveal the expected outcome of pulmonary fibrosis is a logical next step.
Finally, Applicant argue that “Liu does not disclose the knockout of Cdc42 gene in AT2 cells leads to progressive lung fibrosis in PNX-treated animals, nor the progressive lung fibrosis phenotype occurs in non-PNX-treated Cdc42 AT2 null animals in middle age and old age.” (page 16, para 3) and that “mechanical stresses can induce various diseases, […] , but not only pulmonary fibrosis.” (page 16, para 4) such that “one skilled in the art would have not though of the mice which has increased mechanical-tension on the alveolar epithelium, can develop pulmonary fibrosis.” (page 16-17, bridging para).
In response, indeed Liu does not teach that the knockout of Cdc42 gene in AT2 cells leads to progressive lung fibrosis. In the instant rejection, teachings pertaining to utility of Liu’s mouse model in Lv’s method for screening drug candidates for pulmonary fibrosis is provided by Sisson. Additionally, mechanical stress is not recited as the model of pulmonary fibrosis.
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.
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/MATASHA DHAR/Examiner, Art Unit 1632
/EMILY A CORDAS/Primary Examiner, Art Unit 1632