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
The amended claim set filed 27 March 2025 is acknowledged. Claims 21-40 are currently pending. Of those, all claims are new. Claims 1-20 are cancelled. Claims 21-40 will be examined on the merits herein.
Priority
This application claims priority to provisional application 62/640,494 (filed 8 March 2018), is a 371 of PCT/NL2019/050153 (filed 8 March 2019) and is a CON of 16/979,117 (filed 8 Sep 2020). The effective filing date used to search all claims is 08 Mar 2018.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 19 Nov 2024 was filed in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner. A signed copy of the statement is attached with this action. The foreign patent document and NPL document copies that were not provided in this action can be found in the parent application 16/979,117.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 21-40 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. There is no scope within the current claims that is enabled because the claimed functional effect is not enabled for the claimed method.
The factors to be considered in determining whether a disclosure would require undue experimentation include: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01. Although all factors were considered, the Wands factors that were most relevant for this decision are discussed in detail below.
The breadth of the claims: Claim 21 and its dependent claims are methods to treat sepsis-associated acute kidney disease injury (SA-AKI) in a subject in need thereof comprising administering an effective amount of alkaline phosphatase (AP) to the subject, wherein (i) the subject has an ECC (endogenous creatinine clearance) rate < 15 ml/min prior to the treatment with AP or an eGFR (estimated glomerular filtration rate) < 15 ml/min prior to the treatment with AP, (ii) the AP is administered in at least one 500 U/kg to 2,000 U/kg dose, and (iii) the administration of the AP results in an increase in renal function, wherein the AP is a chimeric AP having 100% sequence identity to the amino acid sequence of SEQ ID NO: 1. Dependent claims limit the source of the AP (claim 22), timing (claims 24-27), and dose (claims 31-38) of the administration.
Additional functional limitations are required by dependent claims 23 (“the increase in renal function comprises an increase in ECC with respect to ECC in the absence of treatment or an increase in eGFR with respect to eGFR in the absence of treatment”), 39 (“the administration of at least one dose of AP results in a shortening of duration or cessation of renal replacement therapy (RRT) in a subject undergoing RRT”) and 40 (“the administration of at least one dose of AP results in the preservation or increase of glomerular filtration rate (GFR) or eGFR in the subject”).
Importantly, the claims require the functional effect of “treat sepsis-associated acute kidney disease injury (SA-AKI) in a subject” that “results in an increase in renal function”, as well as additional functional effects for some dependent claims. The claims are broader than what is enabled by the specification because the specification teaches this effect does not occur when the claimed bacteria are administered (see below).
The amount of direction provided by the inventor: The specification teaches that “currently, no approved pharmacologic interventions are available to prevent or treat AKI” [0047] and teaches small clinical trials using bovine AP to improve renal function in patients with sepsis [0047]. The specification teaches that the RecAP protein is a chimeric AP combining two human APs and that it has the benefit of being stable and biologically active [0049]. The specification does not teach that the properties of RecAP in vivo are known in the art. The specification teaches doses that RecAP might be administered at [0092-0093, 0095-0104], but describes a broad range of dosages and administrations and does not disclose which ones are suitable for achieving the claimed functional effects.
The existence of working examples: Example 1 is a study of efficacy and safety when administering recombinant alkaline phosphatase (RecAP) at either 0.4, 0.8, or 1.6 mg/kg, or placebo, once daily for 3 days. RecAP has SEQ ID NO: 1 [0005]. The subjects with <15 ml/min baseline ECC had a significant long term effect resulting in improved survival, but no improvement in improved kidney function (as evidenced by improved creatinine clearance (ECC) with respect to placebo), see Figure 17 and [0052]. Also, the specification states that short-term renal function was not affected by treatment [0051]. The study also performed an analysis of subjects with ≤ 60 ml/min eGFR, not < 15 ml/min as in the claims, and found that “patients that presented with a baseline eGFR<60 ml/min benefit from AP administration with regard to mortality similarly as the ECC<15 ml/min group. See FIG. 22.” [0291]. Finally, the applicant’s data demonstrated that “the requirement of RRT was not significantly affected by RecAP treatment (FIG. 8)” [0274]. Both RRT incidence and RRT-free days were not significantly different in the RecAP treatment and placebo control groups (Figure 8).
Example 2 determines the RecAP enzyme activity and protein concentration in vitro, and does not address the protein’s in vivo function(s).
In summary, for the functional limitation of “increase in renal function” from claim 21, the provide specific evidence that there is no short-term increase in renal function or long-term increase in renal function, as measured by ECC levels in the claimed subject population. For the functional limitation “the increase in renal function comprises an increase in ECC with respect to ECC in the absence of treatment or an increase in eGFR with respect to eGFR in the absence of treatment” from claim 23, the examples provide specific evidence that there is no increase in ECC in the claimed subject population, and there is no evidence that eGFR was increased because it was not measured in the claimed subject population. Similarly, for the functional limitation “the administration of at least one dose of AP results in the preservation or increase of glomerular filtration rate (GFR) or eGFR in the subject” from claim 40, the eGFR and GFR in the claimed subjects were not measured after AP administration so there is no evidence that this marker of kidney function has the claimed outcome in the claimed subject population. For the functional limitation “the administration of at least one dose of AP results in a shortening of duration or cessation of renal replacement therapy (RRT) in a subject undergoing RRT” from claim 39, the examples provide specific evidence that this outcome does not occur.
The state of the prior art and the level of predictability in the art: Relevant art at the time of filing is discussed below:
Peters et al. (2016; IDS filed 19 Nov 2024, additional copy enclosed with this action; hereafter Peters) and Kiffer-Moreira et al. (2014; IDS filed 19 Nov 2024, additional copy enclosed with this action; hereafter Kiffer-Moreira). Peters teaches a trial investigating the safety and efficacy of a AP treatment for SA-AKI (Abstract). Subjects “will receive one of the following three doses of recAP: 0.4 mg/kg (250 U/kg), 0.8 mg/kg (500 U/kg) or 1.6 mg/kg (1000 U/kg)” (pg. 5 col. 2 par. 3), so the medium and high dose range fall within the claimed range. Peters states that RecAP was developed by ref. 13 (Kiffer-Moreira, see pg. 2 col. 1 par. 3). An alignment of SEQ ID NO: 1 with the RecAP sequence found in Kiffer-Moreira (Figure 2, referred to as ChimAP) found that the sequences only shared 98.6% identity (see alignment on following page).
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Arend et al. (US-20140219984-A1; hereafter Arend; IDS filed 19 Nov 2024) teaches the use of AP “for preserving renal function after a treatment with a risk of reducing renal function” [Abstract] such as those that “can be so stressful to the kidneys that it results in acute kidney injury (AKI)” [0002]. Specifically AP can be used in sepsis patients [section heading found above par. 0114]. Arend teaches that the average creatine clearance (ECC) in the treated patients is 50 mL/min [Table 2 found after par. 0114], so most of the patients studied had an ECC rate less than or equal to 60 mL/min. The subject has an estimated GFR (eGFR) that is “most preferably less than about 35 mL/min per 1.73 m3” [0028]. This would include subjects that have eGFR that is in the range of less than 15 mL/min. The method comprises administering AP to the subject [0067, 0116]. “As a starting point 10-500 U/kg/day can be used” [0092], so the AP may be administered in at least one 500 U/kg dose. Arend teaches that the method is for increasing GFR and preferably renal creatine clearance [0053]. Specifically, Arend demonstrates that administration of AP, though in a lower dose than claimed, results in increased creatine clearance [0135-0136, Figure 5]. However, Arend teaches a chimeric AP sequence (SEQ ID NO: 5) that only has 99.4% identity to SEQ ID NO: 1 (see Alignment on next page).
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Raaben et al. (US-20170009216-A1; published 12 Jan 2017; hereafter Raaben; IDS filed 19 Nov 2024) teaches alkaline phosphatases with improved properties [0001]. Raaben teaches that the improved alkaline phosphatase is termed “LVL-RecAP” and has SEQ ID NO: 1 [0112]. The alignment of Raaben SEQ ID NO: 1 with instant SEQ ID NO: 1 is shown on the next page; the two sequences have 100% identity. Raaben teaches that LVL-RecAP has advantages including increased stability in several different conditions [0128, 0135, 0144] and increased affinity for the substrate PLP at physiologic pH [0143]. Raaben teaches that the LVL-RecAP protein can be used in acute kidney injury [0051-0052], and teaches that their protein is especially useful in sepsis-related conditions because it remains active in Zn2+- deficient environments while other alkaline phosphatases lose their activity [0032]. Among other examples, Raaben teaches the pharmacokinetic distribution of LVL-RecAP [Example 4], teaches that LVL-RecAP is protective in a pig model of kidney disease [Example 6, 0236], and teaches that LVL-RecAP administration to humans in doses of 200 U/kg to 2000 U/kg [0241] does not produce any serious adverse events [Example 7, 0254]. Raaben teaches the LVL-RecAP protein is derived from human alkaline phosphatases [0100].
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In summary, the art at the time of filing teaches that alkaline phosphatases with greater than 90% identity to the instant SEQ ID NO: 1 were known in the art (Kiffer-Moreira, Arend) and that these proteins can be used in sepsis-associated acute kidney injury (SA-AKI) at the claimed dosages (Peters, Arend). The exact protein of SEQ ID NO: 1 was also known (Raben), but the teaching to use the protein with kidney injury or SA-AKI is more general and does not disclose any specifics. The Peters and Raben references are both prophetic for treating SA-AKI. None of the references point out subjects with an ECC (endogenous creatinine clearance) rate < 15 ml/min prior to the treatment with AP or an eGFR (estimated glomerular filtration rate) < 15 ml/min prior to the treatment with AP or teach that the AP protein would be effective at increasing renal function, increasing ECC or eGFR compared to the absence of treatment, resulting in a shortening of duration or cessation of renal replacement therapy (RRT), or resulting in the preservation or increase of glomerular filtration rate (GFR) or eGFR in the subject.
The nature of the invention and the quantity of experimentation needed to make or use the invention: The nature of the invention requires in vivo treatment of SA-AKI in a specific patient population by administering a specific AP protein resulting in an increase in renal function, and additional functions in dependent claims such as increasing ECC or shortening the duration of RRT. There is specific evidence from both the specification and art that SEQ ID NO: 1 AP protein does not have these effects in the claimed patient population.
There is no amount of experimentation that will change the properties of AP protein. The amount of experimentation required for enabling guidance, commensurate in scope with what is claimed, goes beyond what is considered ‘routine' within the art, and constitutes undue further experimentation in order to use the method with a reasonable expectation of successfully increasing renal function, increasing ECC or eGFR, shortening the duration of RRT, or preserving or increasing GFR or eGFR. Therefore, claims 21-40 are rejected under 35 U.S.C. §112(a) or 35 U.S.C. §112, first paragraph, for failing to meet the enablement requirement. However, it is noted that the claimed therapy was found to reduce mortality in the claimed patient population (see Figure 17), which is not currently a claimed function.
Claims 21-40 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.
The claimed invention, the teachings of the specification, and the teachings of the art are discussed in the enablement rejection above. MPEP 2163 states: “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.” In this case, the examples specifically demonstrate that the claimed administration to the claimed subject population does not have the claimed effects. Therefore, the applicant’s data demonstrates that the applicant lacks possession of a treatment method that has the functional effects required by the claims.
Conclusion
No claims are allowed.
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AMELIA N DICKENS
Examiner
Art Unit 1645
/AMELIA NICOLE DICKENS/Examiner, Art Unit 1645
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