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, 27, 28, 29 are pending and examined here.
Priority
The claim for benefit to the U.S. Provisional application 62/329,955 filed on 4/29/2016 is recognized. All the examined claims enjoy the benefit of ‘955 filing date.
Claim Rejections - 35 USC § 103
Rejection of claims 1, 27, 28, and 29 is maintained.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 27, 28, 29 are rejected under 35 U.S.C. 103 as being unpatentable over
Appleman and Thompson (US20150224132, pub. 08/13/2015, referred as Appleman, cited in prior Action) and Cabrera-Benitez et al. (2014, Anesthesiology, 121, 189-198) and Li et al. (2015, Cell. Physiology and Biochem., pg. 2403-2417).
The specification defines “prevent” to encompass obtaining beneficial or desired results (par. 45), which includes some beneficial or desired results.
Appleman discloses a method of treating pulmonary fibrosis by administering to a subject a therapeutically effective amount of a modulator that specifically targets PERK, also known as eIF2AK3 (eukaryotic translation initiation factor 2-alpha kinase 3), and one modulator noted is a siRNA that targets eIF2AK3 (par. 6, 66-67). Pulmonary fibrotic disease is characterized by fibrosis of lung tissue (par. 54) and is “characterized by fibrotic lesions, progressive distortion of alveolar architecture occurs and replacement with fibrotic or scar tissues with excess ECM [extracellular matrix] deposition” (par. 26). Appleman discloses pulmonary route of administration, thus treating epithelial cells of the lung (par. 131).
Appleman does not disclose a method of preventing VILI to a subject with VILI and wherein VILI is caused by damage to epithelial barrier, which is caused by alveolar overdistention.
Cabrera-Benitez et al. disclose that mechanical ventilation, although a critical supportive therapy for patients with acute respiratory distress syndrome, and VILI, “maybe a major contributor to lung fibrosis,” which may lead to morbidity and mortality (pg. 189, Abstract). Further, Cabrera-Benitez et al. disclose both pronounced epithelial and endothelial injury (pg. 190) and indicate that “mechanical ventilation maybe a key driver of the fibroproliferative response” (pg. 190) and thus suggest a two factor response, a) removal of mechanical ventilation as early as possible maybe a key factor in enabling normal lung repair and b) attenuating the fibroproliferative response for improving patient survival (pg. 190).
Further, mechanical ventilation with high pressures can lead to barotrauma, which is air leaks caused by overdistension, leading to volutrauma, which is characterized by increased alveolar-capillary leak (pg. 191, relevant to instant cl. 28). Describing the effects at the cellular level, Cabrera-Benitez et al. disclose that mechanical stretch of alveolar epithelial cells “can result in loss of tight junction structure and cell-cell attachment” (pg. 191, see figure below), thus causing damage to the epithelial barrier (relevant to instant cl. 27).
Figure from Cabrera-Benitez (pg. 191)
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At the molecular level, Cabrera-Benitez disclose the release of TGF-β by alveolar type II (ATII) cells, also epithelial type II cells (fig. 3, pg. 190); activation of TGF-β is noted in response to in vitro mechanical stretch in lung epithelial cells and thus involved in development of pulmonary fibrosis (pg. 192).
Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the filing date of the claimed invention to have modified the method of administration of siRNA targeting PERK to treat lung fibrosis, characterized by alveolar distortion, of Appleman in view of Cabrera-Benitez et al. and arrive at the claimed invention with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to modify the method of administration of siRNA targeting PERK to treat lung fibrosis of Appleman and administer PERK siRNA to a subject with VILI caused by epithelial barrier damage resulting from overdistension-mechanical damage since VILI results in lung fibrosis due to cellular damage to epithelial tight junction as taught by Cabrera-Benitez to provide for a reasonable expectation of success in treating a subject with VILI.
Regarding instant cl. 29, Appleman discloses that the modulator can be applied before or after fibrotic lesion has developed in the subject (par. 78, cl. 14), and defines fibrotic lesion as focal area of fibrosis.
Since Cabrera-Benitez discloses that mechanical stretch at the molecular level affects cytoskeleton remodeling and plays a role in fibrosis formation, it would be obvious for a skilled artisan to administer the modulator prior to administration of ventilator-induced mechanical stretch or prior to the start of mechanical ventilation to prevent fibrosis formation.
Further, MPEP 2144.04(IV)(C) indicates that selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results. Thus, administering to the subject PERK pathway inhibitor prior to the start of mechanical ventilation is prima facie obvious. Thus, cl. 29 is obvious.
Response to Arguments
Applicant's arguments filed 08/28/2025 (“the Remarks”) have been fully considered but they are not persuasive.
The Remarks argue (1) that “Office still has not established a conclusive link between VILI and fibrosis that would have led one of ordinary skill in the art to arrive at the claimed methods” and indicate that the speculative language of prior art (“may be”) is not sufficient to “establish a link between VILI and fibrosis that can support a proper obviousness rejection” (pg. 3); (2) insist that even if the Office “had met their burden of establishing a link between VILI and fibrosis,” the claims address a “long-felt need” since removal of mechanical ventilation may not be an option for all patients requiring mechanical ventilation (pg. 4); (3) argue that Appleman’s laundry list of potential targets and fibrotic diseases would not have directed a skilled artisan to claimed methods and constitutes an impermissible hindsight reconstruction (pg. 4-5).
The argument is not persuasive.
The arguments (1) and (3) will be addressed together. Appleman discloses what is generally known in the prior art regarding link between VILI and inflammation and fibrosis and what is generally known is not considered a “buried disclosure” when a simple statement will suffice. Curley et al. (2010, American J. of Respiratory and Critical Care Medicine, 181, A1670) presentation titled “Time course of lung injury, inflammation, repair and fibrosis following ventilatory induced lung injury” provide a conclusion based on their results that “rat model of repair of VILI demonstrates the potential of excessive lung stretch to contribute to fibroproliferation in ARDS.” Further, Cabrera-Benitez clearly states that “[i]ncreasing evidence from experimental and clinical studies suggest that mechanical ventilation. . . . can cause lung fibrosis” (abstract). Thus, the link between mechanical ventilation (excessive lung stretch and VILI) and resulting injury (fibroproliferation/fibrosis) is generally known in the art and is not speculative.
Further, Li reference provides a link between PERK siRNA inhibitor and alveolar epithelial cell damage, a prominent feature of acute lung injury, a phenotype of VILI, and ARDS. Li demonstrate that pre-treating with siRNA complementary to PERK increased viability of LPS-treated alveolar cells, a model for acute respiratory distress syndrome (ARDS) (pg. 2412-2413, see also pg. 8 of 02/23/2023 action).
Additionally, as references allude, there is a difficulty in separating a patient in need of mechanical ventilation due to a disease and the disease itself, e.g. acute respiratory distress syndrome (ARDS). As Cabrera-Benitez discloses that mechanical ventilation is the most supportive therapy for patients with ARDS, but the mechanical ventilation itself induce and aggravate lung injury (pg. 1), as the Remarks also point out. Thus, both the disease and its therapy is associated with an inflammatory response, which also means that based on cited references that it would be obvious for a skilled artisan to treat a patient with ARDS, i.e. before mechanical ventilation, and throughout the mechanical ventilation with siRNA targeting PERK, since it aids in cell survival. The increase in cell survival is also noted by instant specification also: Perk pathway inhibition mitigates mechanical stretch-induced cell death (Fig. 10, par. 18); thus the instant results are not unexpected based on the teachings of cited references.
Regarding argument 2, the long-felt need is noted in the references and provide motivation for combining the teachings of cited references and the argument does not aid in overcoming the obviousness rejection: see Li, “[t]hese findings may provide potential clues for exploiting possible therapeutic drugs for the management of alveolar epithelial cell death during ALI” (pg. 2414); Cabrera-Benitez: “(f)uture studies are required to improve our understanding of these mechanisms so that we can develop novel approaches—pharmacologic or other—to prevent or treat the pulmonary fibrosis associated with mechanical ventilation in patients with ARDS” (pg. 9). The teachings/motivation also address the improper hindsight argument (3), 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).
The rejection of examined claims under 103 is maintained.
Allowable Subject Matter
No claim is allowed.
Conclusion
THIS ACTION IS MADE FINAL. 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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/KEYUR A VYAS/Examiner, Art Unit 1637
/Soren Harward/Primary Examiner, TC 1600