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 .
Amendments Received
Amendments to the claims were received and entered on 11/24/2025.
Status of Claims
Claims 1-23 are currently pending and under consideration.
Priority
The present application claims status as a 371 (National Stage) of PCT/NL2021/050547 filed on September 9, 2021 and claims priority to international applications EP21178892.2 filed on June 10, 2021 and EP20195269.4 filed on September 9, 2020. Acknowledgment is made of applicant' s claim for foreign priority and papers submitted under 35 U.S.C. 119 (a)-(d). The present application and all claims are being examined with an effective filing date of September 9, 2020. In future actions, the effective filing date may change due to amendments or further review of priority documents.
Withdrawn Rejections
In view of Applicant’s amendments, narrowing the claimed recombinant alkaline phosphatase to sequences having at least 95% sequence identity to SEQ ID NO: 1, rejection of claim 10 under 35 USC § 112(a) is hereby withdrawn.
Maintained Rejections
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.
Claims 1-5, 8-9, 11-21, and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Davidson, J. (US20190298811 A1, cited in the IDS).
Davidson teaches that a PaO2/FiO2 (interchangeable with “P/F”) less than or equal to 200 “allows for diagnosis of acute respiratory distress syndrome”, while a ratio of 200-300 indicates acute lung distress, and a P/F ratio equal to or greater than 300 indicates “normal lung function” (Specification, para 0199).
Regarding claims 1-4, Davidson discloses administration of bovine intestinal alkaline phosphatase, (BiAP) to animals subjected to cardiopulmonary bypass with deep hypothermic circulatory arrest (DHCA), a model known to induce systemic inflammation and lung injury (Example 6, para 0195-200). Table 22 (Specification, pg. 20) shows that DHCA control subjects developed PaO2/FiO2 (interchangeable with “P/F”) ratios below 200, consistent with a diagnosis of acute respiratory distress syndrome (ARDS), while animals treated with BiAP maintained higher ratios, even reaching normal P/F ratios, suggesting a protective effect against the progression to ARDS. Davidson’s demonstration that alkaline phosphatase prevents progression of lung injury and maintains normal P/F ratios would have reasonably suggested administration of alkaline phosphatase to subjects already meeting ARDS diagnostic criteria, as treatment and prevention represent predictable therapeutics applications along the same disease continuum.
An invention would have been obvious to a person of ordinary skill in the art if some teaching in the prior art would have led that person to arrive at the claimed invention. Before the effective filing date of the claimed invention, Davidson teaches that high dose subjects (i.e., study ID number 13) maintained or recovered “normal lung function” after 4 hours of BiAP treatment, whereas untreated control subjects developed ARDS with P/F ratios dropping into the 100s. Given this demonstrated ability to prevent or attenuate the condition in a relevant preclinical model, it would have been obvious to a person of ordinary skill in the art to apply BiAP in the treatment of subjects already meeting diagnostic criteria for moderate or severe ARDS. A skilled practitioner would have had a reasonable expectation of success in treating moderate and/or severe ARDS in such subjects, by administering an effective amount of alkaline phosphatase because Davidson successfully demonstrates that subjects receiving alkaline phosphatase therapy maintained lung function and avoided decline to ARDS, whereas untreated subjects exhibited decreasing P/F ratios and did progress to ARDS. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Regarding claims 5, 8-9, 14-18, Davidson discloses therapeutic use of AP, including BiAP, as well as “a biologically effective fragment, derivative, conjugate and/or recombinant form thereof” (para 0008, 0035, and 0067). Davidson also discloses the therapeutic use of human AP, as well as “a biologically effective fragment, derivative, conjugate and/or recombinant form thereof” (para 0007, 0010, 0035, 0066, 0072-0073, 0077, etc.) Accordingly, a person of ordinary skill in the art would have found it obvious to use recombinant human or recombinant bovine AP, in the treatment of the same conditions (see MPEP 2144.06, “Substituting equivalents known for the same purpose”). With respect to dosage, Davidson further teaches a broad range of effective dosing regimens (para 0080-0081), including 0.1 to 5000 mg/kg or 0.1 to 5000 U/kg per day, and administration as bolus injection, continuous infusion, or in divided daily doses. Davidson also teaches that “dosage regimens may be adjusted to provide the optimum therapeutic response”, and provides guidance that divided or staggered daily dosing is appropriate. It would have been obvious to one of ordinary skill in the art to administer AP in once daily or three times daily regimens, and to use doses such as 500 or 1000 U/kg, up to 2000 U/kg, or 0.8 or 1.6 mg/kg, within the disclosed effective range. Pursuant to MPEP 2144.05, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).
Regarding claims 11, 19, and 23, Davidson teaches the administration of BiAP to subjects undergoing CPB and DHCA, as described above. Table 22 illustrates that untreated control subjects developed decreasing P/F ratios, dropping below 200 within 2-4 hours post DHCA, consistent with the development of ARDS. In contrast, subjects treated with BiAP maintained higher P/F ratios throughout the study period, including preserved or improved lung function. Accordingly, Davidson teaches that the administration of AP leads to the preservation or increase of P/F ratios relative to the absence of AP treatment, and thereby to an increase in respiratory function. It would have been obvious to a person of ordinary skill in the art that administering AP in similar clinical circumstances would yield improved respiratory outcomes, and that the P/F ratio would improve or be maintained in comparison to untreated subjects. Therefore, the claimed subject matter would have been prima facie obvious before the effective filing date of the claimed invention.
Regarding claim 12, in the DHCA study described above, “subjects were initially subjected to neck cannulation (internal jugular and common carotid), then cooled to 22° C. and kept at that temperature for 75 minutes under complete circulatory arrest. The subjects were then rewarmed to standard body temperature on CPB and kept intubated for 4 hours. Sham-only subject were subjected only to the neck cannulation (not the CPB or drug administration). DHCA control subjects were subjected to CPB and DHCA without receiving BiAP. High dose BiAP subjects were exposed to CPB with DHCA and high dose biAP (75 U/kg iv bolus followed by continuous infusion of 25 U/kg/hr)” (para 0196). As evidenced in Table 22, subjects developed P/F ratios below 200, consistent with a diagnosis of ARDS, within 2-4 hours after rewarming. Thus, Davidson teaches or suggests initiating BiAP treatment during the very early phase of lung injury - including at or shortly after the time that ARDS would become diagnosable based on P/F ratio – and well within a 48 hour window. It would have been obvious to a person of ordinary skill in the art to administer AP within 48 hours of ARDS detection in order to prevent further respiratory decline, given the known rapid progression of ARDS and the acute setting of the Davidson model. Therefore, the claimed subject matter would have been prima facie obvious before the effective filing date of the claimed invention.
Regarding claims 13, and 20-21, as described above, Davidson teaches that treatment with AP following CBP and DHCA in infant piglets, results in significantly improved pulmonary function compared to untreated controls. As shown in Table 22, BiAP treated animals maintained substantially higher P/F ratios throughout the study, even recovering normal lung function, indicating preserved respiratory function and prevention of ARDS and/or its progression. A person of ordinary skill in the art would have understood that such improvements in pulmonary function are associated with reduced duration of mechanical ventilation, as the P/F ratio is a standard clinical marker used to assess readiness for ventilator weaning. It would have been obvious to a skilled practitioner to expect that administration of AP would results in a shortened duration of mechanical ventilation in ARDS patients due to its demonstrated lung-protective effects. Similarly, said practitioner would have had a reasonable expectation that improving respiratory function and preventing severe ARDS would reduce the risk of mortality in individual subjects and improve the overall mortality rate in a population. Davidson’s data supports that BiAP mitigates a key pathophysiological driver of mortality in critical illness (i.e., respiratory failure). Therefore, it would have been obvious to expect that AP treatment could reduce mortality in subjects at risk. Accordingly, the claimed subject matter would have been prima facie obvious before the effective filing date of the claimed invention.
Claims 6, 10 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Davidson, as applied to claims 1 and 9 above, and further in view of Raaben et al. (US Patent No. 9926544 B2, cited in the IDS).
The teachings of Davidson, as they apply to claims 1 and 9, have already been discussed above. Briefly, Davidson discloses administering alkaline phosphatase, including recombinant forms, to improve pulmonary function in subjects exhibiting acute respiratory injury, and provides both dosage and administration details suitable for therapeutic use. Davidson further discloses that treatment with AP has therapeutic effects on organ dysfunction, inflammation, and blood coagulation, all of which are features commonly associated with sepsis-induced ARDS.
Regarding claim 10, Raaben et al. discloses a recombinant alkaline phosphatase (i.e., LVL-RecAP) set forth in SEQ ID NO: 1, having 100% sequence identity to instant SEQ ID NO: 1 (see sequence alignment in the non-final rejection of 07/24/2025). Raaben et al. further teaches polypeptides having at least 90% sequence identity to SEQ ID NO: 1 (Specification, column 2, lines 47-55).
Regarding claims 6 and 22, Raaben et al. explicitly teaches the LVL-RecAP protein as a soluble chimeric human alkaline phosphatase (column 37, lines 25-30), providing a detailed formulation suitable for therapeutic administration. Importantly, Raaben et al. expressly states that the proteins according to the invention (i.e., chimeric AP, SEQ ID NO: 1) are useful as medicaments for a variety of conditions, including inflammatory lung disease, asthma, COPD, infection and sepsis (column 8, lines 3-19). This supports the therapeutic relevance of the chimeric LVL-recAP in pulmonary disorders of the type addressed by Davidson.
An invention would have been obvious to a person of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, it would have been obvious to a person of ordinary skill in the art to employ a recombinant, chimeric alkaline phosphatase protein, such as the LVL-RecAP disclosed in SEQ ID NO: 1 of Raaben et al., for use in the treatment of ARDS. Based on the combined teachings of Davidson and Raaben et al., said practitioner would have had a reasonable expectation of success, as Davidson teaches that AP administration improves lung functions and P/F ratios in subjects exhibiting acute lung injury, while Raaben et al. describes therapeutic use of the LVL-RecAP, including in inflammatory lung disease. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Davidson, as applied to claim 1 above, and further in view of Luyt et al. (Virus-induced acute respiratory distress syndrome: epidemiology, management and outcome. Presse Med. 2011 Dec;40(12 Pt 2):e561-8, cited it PTO-892).
The teachings of Davidson, as they apply to claim 1, have already been discussed above. Briefly, Davidson discloses administering alkaline phosphatase, including recombinant forms, to improve pulmonary function in subjects exhibiting acute respiratory injury. Davidson discloses that AP administration in subjects undergoing DHCA results in attenuation of lung injury and prevention of PF ratios dropping into ARDS diagnostic ranges, as evidenced by untreated control subjects that demonstrated higher P/F ratios. Davidson further states that AP has therapeutic benefits in treating inflammation, blood coagulation disorders, and organ dysfunction, which are all characteristic of ARDS pathophysiology.
Regarding claim 7, Luyt et al. teaches that ARDS may arise from various viral infections, including seasonal and pandemic respiratory viruses (e.g., H5N1 and H1N1 2009), and nosocomial pathogens such as HSV and CMV. Luyt et al. notes that these viruses may cause severe pneumonia evolving into ARDS, and that such patients are often mechanically ventilated (Summary). With respect to treatment, Luyt et al. discloses the use of the anti-viral medication acyclovir, also stating that it has not been specifically evaluated for ARDS treatment, and highlights the nonspecific nature of ARD symptoms, and thus ARDS management (pg. e562-e563). Furthermore, Luyt et al. teaches that the ventilatory management of virus-induced ARDS is the same as for ARDS of other etiologies (pg. e566), suggesting that clinicians treat them similarly despite difference in underlying cause.
An invention would have been obvious to a person of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, in light of the shared, nonspecific clinical features (e.g. , inflammation and pulmonary injury) of ARDS, it would have been obvious to a person of ordinary skill in the art to apply known therapies for ARDS (e.g., alkaline phosphatase) in the context of virus-induced ARDS. It would have been obvious to a person of ordinary skill in the art, to apply the AP treatment taught by Davidson to virus-induced ARDS, based on the clinical parallels and management consistency described by Luyt et al. Said practitioner would have had a reasonable expectation of success given the protective effects observed in Davidson’s preclinical model of inflammatory lung injury. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Response to Arguments for Rejections under 35 USC § 103
In the response filed on 11/24/2025, Applicant argues that Davidson does not teach treatment of subjects already having moderate or severe acute respiratory distress syndrome (ARDS) with a P/F ratio ≤200 mmHg because the treated animals described in Davidson initially exhibited higher P/F ratios. Applicant further asserts that Davidson therefore fails to disclose or suggest administration of alkaline phosphatase to subjects already meeting ARDS diagnostic criteria. These arguments have been fully considered but are not persuasive.
Davidson expressly discloses a cardiopulmonary bypass/deep hypothermic circulatory arrest model known to induce systemic inflammation and lung injury resulting in ARDS. As shown in Table 22, untreated control subjects exhibited declining P/F ratios falling below 200 mmHg, consistent with development of ARDS, whereas subjects receiving alkaline phosphatase maintained higher P/F ratios and preserved lung function. Thus, Davidson demonstrates that alkaline phosphatase therapy mitigates the same ARDS disease process and prevents progression to severe respiratory impairment. Because Davidson demonstrates that subjects receiving alkaline phosphatase therapy maintained lung function and avoided decline to ARDS while untreated subjects progressed to ARDS, a person of ordinary skill in the art would reasonably have expected alkaline phosphatase administration to provide therapeutic benefit in subjects already exhibiting moderate or severe ARDS. Pursuant to MPEP 2143.02 II., obviousness does not require absolute predictability, but at least some degree of predictability. The claimed limitation directed to subjects having a P/F ratio ≤200 mmHg therefore represents a predictable application of the known therapy across the same disease continuum rather than a patentable distinction.
Applicant’s reliance on Juscheten et al., a reference not relied upon in the rejection, has been considered but is not persuasive because the reference was published after the effective filing date of the claimed invention and therefore does not reflect the state of the art available to a person of ordinary skill in the art at the time of the invention. Obviousness and reasonable expectation of success must be evaluated based on knowledge available as of the effective filing date. Moreover, even if considered, Juscheten et al. discusses endogenous enzyme activity and reports experimental results using a particular recombinant alkaline phosphatase in an acute murine lung injury model. Notably, Juscheten et al. acknowledges in its background discussion that alkaline phosphatase has recognized anti-inflammatory effects, notwithstanding the experimental findings reported for the acute murine lung injury model described therein. At most, the reference reflects variability in reported outcomes, which would not have negated the expectation of success supported by the affirmative therapeutic results demonstrated in Davidson. And with respect to amended claim 10, the amendment requiring at least 95% sequence identity to SEQ ID NO:1 does not overcome the rejection because Raaben et al. expressly discloses a recombinant alkaline phosphatase having 100% sequence identity to SEQ ID NO:1, which falls within the amended claim scope.
Accordingly, the rejections of claims 1–23 under 35 U.S.C. §103 are maintained.
Conclusion
No claim is in condition for allowance.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NAGHMEH NINA MOAZZAMI whose telephone number is (703)756-4770. The examiner can normally be reached Monday-Friday, 9:00-5:00.
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/NAGHMEH NINA MOAZZAMI/Examiner, Art Unit 1652
/ROBERT B MONDESI/Supervisory Patent Examiner, Art Unit 1652