DETAILED ACTION
Examiner acknowledges receipt of applicant’s reply filed 07/30/2026, in response to the non-final office action mailed 02/03/2026.
Claims 1, 9, 12, 13, 17, 21, 27-31, 34-40, 63 and 64 are pending. Claim 15 has been canceled.
Claims 1, 9, 12, 13, 17, 21, 27-31, 34-40, 63 and 64 are being examined on the merits in this office 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 .
Specification- withdrawn
The objections to the abstract and specification are withdrawn in view of the amendment filed 7/30/2026.
Claim Objections- withdrawn
The objection to claim 1 is withdrawn in view of the amendment filed 7/30/2026.
Claim Rejections - 35 USC § 112
The rejections of claims 1, 9, 12, 13, 15, 17, 21, 27-31, 34-40, 63 and 64 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph (enablement), is withdrawn in view of the amendment filed 7/30/2026.
The rejections of claims 1, 9, 12, 13, 15, 17, 21, 27-31, 34-40, 63 and 64 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in view of the amendment filed 7/30/2026.
Claim Rejections - 35 USC § 103- withdrawn in part
The rejections of claims 31, 39, and 40 under 35 U.S.C. 103 as being unpatentable over Nuijens (U.S. 2007/0185011 -cited IDS filed 3/23/2023), as evidenced by Nuijens et al (WO01/57079- hereinafter referred to as “Nuijens 2”), in view of Elshabrawy et al (PLOS One 7(11): e50366 (2012)) and Gorbalenya et al (Nat Microbiol 5:536-544 (March 2020)), as applied to claims 1, 9, 15, 17, 21, 27, 28, 63, and 64 above, and further in view of Wygrecka et al. (Am J Resp Crit Care Med 106:186-199 (2017), as evidenced by Riedl (Clin Drug Investig 35:407–417 (2015)), is withdrawn in view of the arguments filed 7/30/2026 asserting that the limitation of decreased below 50% initial pathological status or reached normal values is not expressly taught by the cited references (reply at p. 16).
Response to Arguments
Applicant’s amendment and arguments, filed 7/30/2026, with respect to objections and rejections above have been fully considered and are persuasive. The objections and rejections has been withdrawn.
Applicant's arguments filed 7/30/2026 have been fully considered with respect to the maintained rejections but they are not persuasive.
Upon further consideration, a new ground(s) of rejection is made in view of the amendment filed 7/30/2026.
An action on the merits is set forth herein.
Specification
Please note, the specification has not been checked to the extent necessary to determine the presence of all possible error. Applicant's cooperation is required in correcting any errors of which applicant may become aware in the specification. MPEP § 608.01.
Sequence Interpretation/Claim Interpretation
The Office interprets claims comprising language as relating to sequences: in the following manner: “comprising an amino acid sequence of” requires only a dipeptide or more within the claimed peptide/protein, “comprising the amino acid sequence of peptide/protein” requires the full-length sequence with 100% identity to the peptide/protein with or without additional amino acids at any N-/C-terminal ends or additional nucleotides at 5' /3' ends, “consisting of an amino acid sequence of peptide/protein” would encompass any sequence of two or more consecutive amino acids (dipeptide or more) fully contained within the peptide/protein, and “consisting of the amino acid sequence of peptide/protein”. Please note this interpretation also applies if the “peptide/protein” was identified by a SEQ ID NO.
Please note that the Examiner is interpreting the scope of claim 1 as only requiring a dipeptide (two or more consecutive amino acids contained) within a C1INH protein with or without additional amino acids at the N-/C-terminal ends (the claim recites “the C1INH has [comprising] an amino acid sequence … of endogenous human C1 esterase inhibitor”).
New Rejections
Claim Rejections - 35 USC § 112
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.
Claims 1, 9, 12, 13, 17, 21, 27-31, 34-40, 63 and 64 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. This is a new rejection necessitated by the amendment filed 7/30/2026.
The metes and bounds of claim 1 are deemed to be indefinite. Claim 1 recites a method of treating a patient suffering from respiratory distress, comprising administering a therapeutically effective amount of C1 esterase inhibitor (C1INH) to the patient, wherein the respiratory distress is caused by a coronavirus infection and wherein the C1INH has an amino acid sequence identical or similar to the amino acid sequence of endogenous human C1 esterase inhibitor.
As noted above under claim interpretation, the claim is construed as only requiring a dipeptide/ 2 consecutive amino acids of a human C1 esterase inhibitor. The claims and specification do not refer to a specific sequence of human C1 esterase inhibitor that is used as a baseline/comparative sequence. Specifically, it is unclear if there is a single C1 esterase inhibitor protein, or if there are C1INH protein variants that encompass multiple distinct sequences. The claims and specification further do not provide any definitive guidance as to the amount/level of sequence similarity/identity that is required to maintain sequence similarity/identity with C1INH yet maintain functional utility in a method of treating respiratory distress. Accordingly, the skilled artisan is not apprised of what C1INH sequences fall within the instant claim scope and those that fall outside the claim scope.
Claim clarification is required. To overcome this rejection, Examiner recommends that the claim be amended to recite “has [[an]] the amino acid sequence .. of SEQ ID NO:X” and further recite a percent (%) identity.
Because claims 9, 12, 13, 17, 21, 27-31, 34-40, 63 and 64 depend from indefinite claim 1 and do not clarify the point of confusion, they must also be rejected under 35 U.S.C. 112(b).
Maintained Rejections
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 9, 12, 13, 17, 27-31, 34-40, 63 and 64 remain/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 rejection is maintained from the office action mailed 2/03/2026, but has been amended to reflect claims filed 7/30/2026.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof.
The courts have stated:
“To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.” Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the Application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient.” MPEP 2163.
Further, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co., the court stated:
“A written description of an invention involving a chemical genus, like a description of a chemical species, 'requires a precise definition, such as by structure, formula, [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials. Fiers, 984 F.2d at 1171, 25 USPQ2d at 1606; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284-85 (CCPA 1973) ("In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus. . . ."). Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The MPEP further states that if a biomolecule is described only by a functional characteristic, without any disclosed correlation between function and structure of the sequence, it is “not sufficient characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence.” MPEP 2163. The MPEP does state that for generic claim the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. MPEP 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP 2163. Although the MPEP does not define what constitute a sufficient number of representative, the Courts have indicated what do not constitute a representative number species to adequately describe a broad generic. In Gostelli, the Court determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872 F.2d at 1012, 10 USPQ2d at 1618.
In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant is in possession of and what Applicant is claiming. The Federal Circuit has emphasized that "the hallmark of written description is disclosure" and "[t]hus, ‘possession as shown in the disclosure’ is a more complete formulation." Ariad, 598 F.3d at 1351, 94 USPQ2d at 1172. Accordingly, "the test requires an objective inquiry into the four corners of the specification from the perspective of a person of ordinary skill in the art" and "[b]ased on that inquiry, the specification must describe an invention understandable to that skilled artisan and show that the inventor actually invented the invention claimed." Id.
The instant claims are drawn to a method of treating a patient suffering from respiratory distress, comprising administering a therapeutically effective amount of C1 esterase inhibitor (C1INH) to the patient, wherein the respiratory distress is caused by a coronavirus infection and wherein the C1INH has an amino acid sequence identical or similar to the amino acid sequence of endogenous human C1 esterase inhibitor.
The specification states at para. [0034]:
The terms “C1 Inhibitor,” “C1 esterase Inhibitor,” “C1-INH” and “C1INH” refer to the proteins or fragments thereof that function as serine protease inhibitors to inhibit proteases associated with the complement system, such as proteases C1r and C1s as well as MASP-1 and MASP-2; with the kallikrein-kinin system, such as plasma kallikrein and factor Xlla; and with the coagulation system, such as factor XIa. In addition, C1INH can serve as an anti-inflammatory molecule that reduces the selectins-mediated leukocyte adhesion to endothelial cells. C1INH, as used herein, can be a native serine protease inhibitor or active fragment thereof, or it can comprise a recombinant peptide, a synthetic peptide, peptide mimetic, or peptide fragment that provides similar functional properties—e.g., the inhibition of proteases C1r and C1s, MASP-1, MASP-2, factor Xlla, and/or factor XIa. C1INH, as used herein, includes both plasma-derived C1INH (e.g., purified from human plasma) and recombinantly produced C1INH (e.g., produced in rabbits or cell culture system).
Para. [0034]:Emphasis added.
The specification states at para. [0048]:
In some embodiments, the C1INH has an amino acid sequence that is
similar to the amino acid sequence of human C1INH (i.e., having an amino acid sequence at least 90% identical to human C1INH while retaining C1INH's functional activity.
It is noted that the specification does not define the terms “similar”, “similarity”, “identical” or “identity”. These terms are not expressly defined anywhere in the specification.
As noted above under claim interpretation, the claim is construed as only requiring a dipeptide/ 2 consecutive amino acids of a human C1 esterase inhibitor. The claims and specification do not refer to a specific sequence of human C1 esterase inhibitor that is used as a baseline/comparative sequence. Specifically, it is unclear if there is a single C1 esterase inhibitor protein, or if there are C1INH protein variants that encompass multiple distinct sequences. The claims and specification further do not provide any guidance as to the amount/level of sequence similarity/identity that is required to maintain sequence similarity/identity with C1INH yet maintain functional utility in a method of treating respiratory distress.
Thus, the instant claim scope encompasses treating a respiratory disease caused by a coronavirus infection comprising administering a C1 esterase inhibitor (C1INH) at a minimum 2 consecutive amino acids of endogenous human C1 esterase inhibitor (OR an identical or similar sequence thereof). The level (%) of required similarity/identity required by the claim scope remains unclear.
The examples are limited to Ruconest® (full-length recombinant human C1INH).
Example 1 relates to administration of Ruconest (recombinant human C1INH) to 5 patients with COVID-19 suffering from respiratory distress. Each patient was administered an initial loading dose of 8400 units of C1INH via intravenous injection. Subsequently, each patient was administered 4200 units of C1INH every twelve hours over the next three days via intravenous injection. The example discloses that four out the five patients improved significantly within one day of treatment.
Examples 2 and 3 are prophetic examples of a clinical trial of patients with SARS-CoV-2 infection who will administered Ruconest.
The only C1 esterase inhibitor reduced to practice was Ruconest®. As evidenced by Ruconest Product Characteristics (European Medicines Agency, accessed ema.europa.eu/en/documents/product-information/ruconest-epar-product-information_en.pdf, 2012, Retrieved on 20 September 2018), ruconest contains conestat alfa. Conestat alfa, recombinant human (full-length) complement component 1 (C1) esterase inhibitor (rhC1INH), is an analogue of human C1INH and is obtained from the milk of rabbits expressing the gene encoding for human C1INH. The amino acid sequence of conestat alfa is identical to that of endogenous C1INH (pp. 2, 5, 12).
The working examples are limited to the C1 esterase inhibitor Ruconest®, full-length recombinant human C1INH. The specification does not describe any other homologues, fragments or derivatives, much less what compounds have the same function as being a homologue, fragment or derivative of C1 esterase inhibitor for use in the claimed method of treating respiratory distress related to a coronavirus infection. Description of Ruconest® is not sufficient to encompass numerous other proteins, peptides and fragments of a C1 esterase inhibitors that belong to the same genus. As noted in the specification, the claimed C1 esterase Inhibitor encompass proteins or fragments of varying amino acid compositions, and numerous distinct qualities that make up the genus.
The examples of treatment are limited to Ruconest®. The skilled artisan cannot envision the functional correlations of the genus of homologues, fragments, or derivatives of Ruconest® having less than 100% identity that can be used in the claimed methods of treatment. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description.
The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does "little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate"). Accordingly, it is deemed that the specification fails to provide adequate written description for the genus of the claims and does not reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the entire scope of the claimed invention.
Response to Arguments
Applicant traversed the rejection at p. 11 of the reply filed 7/30/2026. Applicant asserts that claim 1 was amended to incorporate the limitations of claim 15 and asserts that claim 1 defines the claimed C1INH by reference to a precise structural referent, a well-characterized protein of known structure, rather than an open functional genus (reply at p. 11). Applicant further asserts that the specification discloses that C1INH is encoded by SERPING1 and "codes for a protein of 500 amino acids, including a 22 amino acid signal sequence"; "[r]ecombinant human C1INH shares an identical protein structure with plasma-derived C1INH"; and the "similar" amino acid sequence as "having an amino acid sequence at least 90% identical to human C1INH while retaining C1INH's functional activity" (referring to as-filed spec at pp. 3 and 14). Applicant asserts, the claimed C1INH is not an undescribed genus of mimetics or fragments of unknown structure, but rather a well-characterized protein with a defined percent-identity floor relative to a fully sequenced human protein (reply at p. 11).
Examiner has reviewed and considered Applicants arguments but is not persuaded.
Examiner first refers Applicant to the claim interpretation section above, wherein the instant claims only require 2 consecutive amino acids on an endogenous human C1 esterase inhibitor.
Contrary to Applicant’s assertion, the term “similar” is not expressly defined anywhere in the specification. For full disclosure, the section that Applicant that refers to states:
In some embodiments, the C1INH has an amino acid sequence that is
similar to the amino acid sequence of human C1INH (i.e., having an amino acid sequence at least 90% identical to human C1INH while retaining C1INH's functional activity.
Specification at p. 13, para. [0048]. This statement is not construed as defining the claim term similar for claim construction. It is further noted that the specification does not expressly define the terms “similarity”, “identical” or “identity”.
As indicated in the rejection, the specification reduced to practice Ruconest® (full-length recombinant human C1INH protein).
The rejection is maintained for these reasons and those previously made of record.
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.
Claim(s) 1, 9, 17, 21, 27, 28, 63, and 64 remain/are rejected under 35 U.S.C. 103 as being unpatentable Nuijens (U.S. 2007/0185011 - previously cited), as evidenced by Nuijens et al (WO01/57079- hereinafter referred to as “Nuijens 2”- previously cited), in view of Elshabrawy et al (PLOS One 7(11): e50366 (2012)- previously cited) and Gorbalenya et al (Nat Microbiol 5:536-544 (March 2020)- previously cited). The rejection is maintained from the office action mailed 2/03/2026, but has been amended to reflect claims filed 7/30/2026.
Nuijens, Nuijens 2, and the instant application have the same named applicant, Pharming Intellectual Property B.V.
Nuijens teach administration of an effective dose of C1 esterase inhibitor (C1INH) to treat a respiratory disease, such as acute respiratory distress syndrome (ARDS) (e.g., abstract, paras. [0026]-[0029], claims 1, 10). Treatment refers to treatment of individuals who are already with the disorder as well as those susceptible to the disorder (para [0010]). “Individual” refers to any individual, both human and non-human, both young and old, both ill and asymptomatic. Id. Nuijens teach different dosing including 25 U/kg and 50U/kg body weight and different periods (see e.g. figures 1, 2,3, table 2, pages 2-4; claims 11-12). Para [0031] states human C1INH is administered intravenously at a dose of more than 25, 50 or 70 U/kg body weight of the individual, preferably more than 80, 100, 150 or 200 U/kg body weight of the individual. One unit (U) of C1INH is the amount of C1INH present in 1 millilitre of human blood. One such unit corresponds to approximately 275 microgram plasma derived C1INH. Assuming a molecular weight of 110,000 dalton, the concentration in human plasma of C1INH is 2.5 micromol per litre (p. 3). Nuijens states at para. [0026]:
These pharmaceutical compositions may be administered in a number of ways depending on whether local or systemic treatment is desired, the area to be treated and the stability of the active compound. Suitable formulations will depend on the method of administration. The pharmaceutical composition is preferably administered by parenteral administrations, such as for example by intravenous, intra-arterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or by intrathecal or intracranial administration. In a preferred embodiment it is administered by intravenous infusion. Suitable formulations for parenteral administration are known in the art and are typically liquid formulations. These liquid formulations may for example be administered by an infusion pump. The effective dose, i.e. effective concentration and frequency, will depend on the specific pharmaceutical composition which is used, the severity of the condition and the general state of the patient's health. In general, the effective dose of a pharmaceutical composition which is based on a C1INH with a shorter half-life may be found by routine optimization. A suitable starting point is the dose which is used for the equivalent pharmaceutical composition which is based on plasma-derived C1INH. A great advantage of a pharmaceutical composition of the invention is that a high initial doses may be used in treatment, which enhances the likelihood of successful treatment. This high initial dose is possible because the C1INH in the pharmaceutical composition of the invention shows a faster clearance than its natural counterpart.
Nuijens does not expressly teach or suggest that the respiratory distress is caused by a coronavirus infection.
Elshabrawy et al teach that severe acute respiratory coronavirus (SARS-CoV) infection in humans results in acute respiratory distress syndrome (ARDS) (p. 1). Reemergence of SARS in humans remains a credible health threat because of the animal reservoirs. Id. The viral Spike (S) glycoprotein plays an essential role in receptor binding and membrane fusion critical for the virus entry, and contains epitopes that elicit neutralizing Abs. The SARSCoV S protein consists of two functional domains, S1 (amino acids 12–680) and S2 (amino acids 681–1255). The receptor binding domain (RBD) (amino acids 318–510) contained within the S1 domain is required for binding to ACE-2 receptor on the cell surface and is thought to contain the majority of neutralizing epitopes. Id. Elshabrawy et al further teach human monoclonal antibodies against conserved domains of the SARS-CoV spike protein (abstract, discussion).
Gorbalenya et al teach that the coronavirus-associated acute respiratory disease called coronavirus disease 19 (COVID-19) was caused by a coronavirus termed SARS-CoV-2 (abstract, pp. 536, 542).
It would have been obvious to one of ordinary skill in the art to administer a therapeutically effective amount of C1 esterase inhibitor (C1INH) to a patient with a Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection to treat the associated respiratory distress. The skilled artisan would have known that Nuijens expressly taught that C1INH could be administered to treat acute respiratory distress syndrome (ARDS). The skilled artisan would have recognized that ARDS is the respiratory disorder caused by SARS-CoV infections (see Elshabrawy et al and Gorbalenya et al). Nuijens teach that C1INH has an amino acid sequence identical or similar to endogenous human C1 esterase inhibitor (e.g., para. [0031], Exs 1-3). The skilled artisan would have had a reasonable expectation of success because Nuijens further taught effective amounts of C1INH for treatment, as well as routes of administration. KSR International Co. v, Teleflex inc., 50 U.S. 398, 82 USPQ2d 1385 (2007) discloses combining prior art elements according to known methods to yield predictable results, thus the combination is obvious unless its application is beyond that person's skill. "The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results". Id. at 415-16, 82 USPQ2d at 1395.
Additionally, the U.S. Federal Circuit has explicitly stated that in order to make a prima facie case of obviousness, the suggestion and motivation to combine the references need not be explicitly stated in the text of the references. In DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 80 USPQ2d 1641 (Fed. Cir. 2006), the Court writes, “the suggestion test is not a rigid categorical rule. The motivation need not be found in the references sought to be combined, but may be found in any number of sources, including common knowledge, the prior art as a whole, or the nature of the problem itself. In re Dembiczak, 175 F.3d 994, 999 [50 USPQ2d 1614] (Fed. Cir. 1999). As we explained in Motorola, Inc. v. Interdigital Tech. Corp., 121 F.3d 1461, 1472 [43 USPQ2d 1481] (Fed. Cir. 1997), ‘there is no requirement that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.’” See Dystar at 1645. “Our suggestion test is in actuality quite flexible and not only permits, but requires, consideration of common knowledge and common sense.” See Dystar at 1650.
Accordingly, instant claim 1 is rendered obvious.
Regarding claim 9, Elshabrawy et al teach that the coronavirus uses cellular ACE-2 receptor for cell entry (pp. 1, 6). Regarding claim 17, the C1 inhibitor has a half-life which is less than 60% of the half-life of plasma-derived C1 inhibitor. A C1INH with a shorter half-life may result in a better ratio of beneficial effects and adverse reactions. The use of proteins with a shorter half-life allows for the exposure of an individual to an active compound at a certain level for a concise predetermined time span (paras [0012]-[0016]). See also Example 2 discloses pharmacokinetics of the recombinant human C1INH which had a half-life of about 3 hours. Regarding claim 21, Nuijens teach preparation of C1INH isolated from milk of transgenic rabbits as described in WO 01/57079 [cited herein as Nuijens 2]. Nuijens 2 teaches preparation of Ruconest® in the milk of transgenic mammals. See also instant specification at para [0048]). Regarding claim 27, the C1INH is administered at a dose of more than 25 U/kg body weight of the patient (e.g., paras. [0031], Ex 1-3, claim 11). Regarding claim 28, the C1INH is administered at a dose of more than 50 U/kg body weight of the patient (e.g., paras. [0031], Ex 1-3, claim 12). Regarding claim 63, C1 esterase INH (C1INH) may be used to replace human plasma derived C1INH. C1INH may be used for the treatment of individuals suffering from any condition or disease associated with an absolute or relative deficiency of functional C1INH. Such deficiency may result in an insufficient control of C1INH on local or systemic activation of inflammatory systems involved in the pathophysiology of said conditions, including the complement and contact systems (e.g., para. [0029]). Regarding claim 64, Gorbalenya et al teach that the coronavirus-associated acute respiratory disease called coronavirus disease 19 (COVID-19) was caused by a coronavirus termed SARS-CoV-2 (abstract, pp. 536, 542). Gorbalenya et al teach the classification of coronaviruses was largely based on serological (cross-) reactivities [reads on antibodies against SARS-CoV-2] to the viral spike protein (p. 538).
Response to Arguments
Applicant traversed the rejection at pp. 13-16 of the reply filed 7/30/2026. Applicant asserts hindsight and lack of reasonable expectation of success (reply at p. 14).
Applicant asserts that Nuijens is directed to a shorter-half-life C1INH for “transient treatment” and ARDS is only “one item in a long list of twenty disparate conditions” (reply at pp. 14). Applicant asserts that “Nuijens provides no working example or data directed to ARDS or any respiratory condition” and is limited to hereditary angioedema (HAE) patients in a Phase I dosing/pharmacokinetic study. Id. Applicant asserts that a listing including ARDS amongst other diseases doesn’t direct the artisan to treat respiratory diseases caused by a coronavirus infection (reply at p. 15). Applicant asserts that Elshabrawy is directed to human mAbs against the SARS-CoV spike protein and Gorbalenya is a taxonomy paper identifying SARS-CoV-2 as the cause of COVID-19 (reply at p 15). Applicant asserts that neither reference suggests C1INH for any purpose. Applicant alleges the combination of references is “impermissible hindsight resting on … syllogism”. Id. Applicant asserts that ARDS is an etiologically heterogenous syndrome that can result from “numerous” direct and indirect causes, further referring to the cited reference Wygrecka (reply at p. 15). Applicant states: A bare listing of ARDS among twenty conditions, without any data, working example, or mechanistic rationale linking C1INH to viral- etiology ARDS, does not provide a reason to select ARDS from the list, much less to treat ARDS arising specifically from a coronavirus infection. Id.
Applicant next asserts there was no reasonable expectation of success, referring to the unrelated enablement rejection. Applicant states: Applicant submits that these findings [relating to enablement rejection and unpredictability] are inconsistent with, and negate, the reasonable expectation of success and "predictable results" on which the § 103 rejection depends. The Examiner cannot simultaneously maintain that the art is unpredictable for purposes of enablement and that the same art yields predictable results for purposes of obviousness.
Applicant’s arguments with respect to pages 15-16 are set forth below as they relate to the second 103 rejection (further citing Wygrecka and Riedl).
Examiner has reviewed and considered applicants arguments but is not persuaded.
Of note, Nuijens and Nuijens 2 are Applicant’s own prior art. Thus, arguments minimizing the teachings of Nuijens undermine the teachings of Applicants own prior work.
Applicant’s assertion that ARDS is merely listed in Nuijens and there is no data or working examples in the reference, places requirements on a prior art reference that are not required by MPEP guidelines.
Examiner reminds Applicant that patents and applications are relevant as prior art for all they contain. "The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain." In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983). A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). Nonpreferred embodiments constitute prior art. See M.P.E.P. §2123.
It would have been obvious to one of ordinary skill in the art to administer a therapeutically effective amount of C1 esterase inhibitor (C1INH) to a patient with a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection to treat the associated respiratory distress.
Nuijens expressly taught administration of an effective dose of C1 esterase inhibitor (C1INH) to treat a respiratory disease, such as acute respiratory distress syndrome (ARDS) (e.g., abstract, paras. [0026]-[0029], claims 1, 10). Nuijens taught that C1INH has an amino acid sequence identical or similar to endogenous human C1 esterase inhibitor (e.g., para. [0031], Exs 1-3). Elshabrawy and Gorbalenya further taught that severe acute respiratory coronavirus (SARS-CoV) infection in humans results in acute respiratory distress syndrome (ARDS). Thus, patients with ARDS (e.g., patients with SARS-CoV infection, as taught by Elshabrawy and Gorbalenya) were the exact patient population that Nuijens sought to treat with C1INH. The suggestion and motivation to combine the references need not be explicitly stated in the text of the references. In DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 80 USPQ2d 1641 (Fed. Cir. 2006), the Court writes, “the suggestion test is not a rigid categorical rule. The motivation need not be found in the references sought to be combined, but may be found in any number of sources, including common knowledge, the prior art as a whole, or the nature of the problem itself. In re Dembiczak, 175 F.3d 994, 999 [50 USPQ2d 1614] (Fed. Cir. 1999). As we explained in Motorola, Inc. v. Interdigital Tech. Corp., 121 F.3d 1461, 1472 [43 USPQ2d 1481] (Fed. Cir. 1997), ‘there is no requirement that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.’” See Dystar at 1645. “Our suggestion test is in actuality quite flexible and not only permits, but requires, consideration of common knowledge and common sense.” See Dystar at 1650.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Regarding reasonable of expectation, Examiner expressly notes the enablement rejection (withdrawn herein) related to prevention language (see OA mailed 2/03/2026 at p 10). The instant 103 rejection is not based on prevention language. Here, Nuijens taught that C1INH could be used to treat ARDS. Elshabrawy and Gorbalenya further taught that severe acute respiratory coronavirus (SARS-CoV) infection in humans results in acute respiratory distress syndrome (ARDS). Thus, it would have been obvious to treat SARS-CoV patient (e.g. patients with ARDS) with C1INH to thereby treat the ARDS in the SARS-CoV infected patients. Examiner reiterates this is a different analysis than the enablement rejection (withdrawn herein) relating to prevention.
MPEP guidelines require a “reasonable” expectation of success, there is no requirement of a guarantee of success. Conclusive proof of efficacy is NOT required to show a reasonable expectation of success. Acorda Therapeutics, Inc. v. Roxane Lab., Inc., 903 F.3d 1310, 1333, 128 USPQe2d 1001, 1018 (Fed. Cir. 2018) ("This court has long rejected a requirement of ‘[c]onclusive proof of efficacy’ for obviousness." (citing to Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014); PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1364 (Fed. Cir. 2007); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364, 1367-68 (Fed. Cir. 2007) (reasoning that "the expectation of success need only be reasonable, not absolute")). See MPEP § 2143.02.
Accordingly, the rejection is maintained at least for these reasons and those previously made of record.
Claims 1, 9, 12, 13, 17, 21, 27-30, 34-38, 63 and 64 remain/are rejected under 35 U.S.C. 103 as being unpatentable over Nuijens (U.S. 2007/0185011 - previously cited), as evidenced by Nuijens et al (WO01/57079- hereinafter referred to as “Nuijens 2” - previously cited), in view of Elshabrawy et al (PLOS One 7(11): e50366 (2012- previously cited)) and Gorbalenya et al (Nat Microbiol 5:536-544 (March 2020) - previously cited), as applied to claims 1, 9, 17, 21, 27, 28, 63, and 64 above, and further in view of Wygrecka et al. (Am J Resp Crit Care Med 106:186-199 (2017)- previously cited), and Riedl (Clin Drug Investig 35:407–417 (2015) - previously cited). The rejection is maintained from the office action mailed 2/03/2026, but has been amended to reflect claims filed 7/30/2026.
Nuijens, Nuijens 2, and the instant application have the same named applicant, Pharming Intellectual Property B.V.
The teachings of Nuijens, Nuijens 2, Elshabrawy et al, and Gorbalenya et al are set forth above. Nuijens teach that C1INH has an amino acid sequence identical or similar to endogenous human C1 esterase inhibitor (e.g., para. [0031], Exs 1-3).
While Nuijens teach treating ARDS with C1NH, and Elshabrawy et al and Gorbalenya et al teach that SARS-CoV/ SARS-CoV-2 infection cause ARDS, the references do not explicitly teach ventilators as being associated with the treatment of ARDS.
Wygrecka et al. teach that acute respiratory distress syndrome (ARDS) is a life-threatening condition characterized by an acute onset, bilateral opacities following chest imaging, pulmonary edema, and severe hypoxemia. Etiologically, ARDS can result from several direct and indirect causes. Reducing the detrimental effects of ventilation currently represents the most important measure taken to combat the effects of ARDS. ARDS may resolve completely after the acute phase or culminate in pathologic tissue remodeling and fibrotic alteration of the lung. Reducing the detrimental effects of ventilation currently represents the most important measure taken to combat the effects of ARDS (p. 187). Wygrecka et al. teach that 46 patients with moderate to severe ARDS were investigated (direct ARDS, n = 28; indirect ARDS, n = 18). Id.
Wygrecka et al. teach the effect of C1INH administration on fibrin formation in vivo. However, no changes in fibrin(ogen) and D-dimer levels and the BALF clotting time between bleomycin-treated animals that received C1INH and those that obtained vehicle were observed (Figures 2A–2D) (pp. 187-188). Wygrecka et al. teach that importantly, administration of C1INH into bleomycin-challenged B1-/-/B2-/- animals preserved lung structure; reduced leukocyte and neutrophil counts in BALF; and diminished TNF-a, IL-1b, and IL-6 expression as compared with B1-/-/B2-/- littermates receiving vehicle (Figures 2F–2H, 2K, 2L, and E3C). This indicates that C1INH may attenuate inflammatory responses independently of the kallikreinkinin system (p. 192). Application of C1INH or antihistone antibodies (αHis) conferred cytoprotection; however, when given simultaneously no additive effect was observed implying that C1INH and αHis use a similar mechanism to inhibit cell death (Figures 3B and 3C). The protective effect of C1INH was dose dependent and did not rely on its protease inhibitory activity because reactive center-cleaved C1INH (iC1INH) and heat denatured C1INH were able to block histone- or NET-mediated cell death (Figures 3D and 3E). Moreover, the cytoprotective effect of C1INH, iC1INH, and denatured C1INH was also observed when primary mouse alveolar type II cells and human lung microvascular endothelial cells were exposed to histones or NET (Figures 3F and 3G) (pp. 192, 196-197). Wygrecka et al. teach disclose the use of C1INH2 in treating ARDS (abstract, pp 196-197).
Riedl evidences that C1 esterase inhibitor (C1-INH) is administered to patients suffering from Hereditary angioedema (HAE) at 50 IU/kg with 2 doses every 24 hrs. This is a routine dosage approved by the FDA in 2014. Although the frequency of attacks can vary considerably in untreated patients (every 7–14 days on average), individual HAE attacks generally follow a predictable clinical course of symptoms developing gradually during the first 24 h and then subsiding during the subsequent 48–72 h (Table 1; p. 408-409). Thus, teaching an administration routine for at least 96 hours. Population pharmacokinetic analysis of rhC1-INH supports an intravenous dosing strategy of 50 U/kg (maximum 4200 U) (Riedl at abstract, p 410, Tables 1-2).
It would have been prima facie obvious to one skilled in the art to combine the teachings of above references because Wygrecka et al. teach that ARDS is a life-threatening condition characterized by an acute onset and administration of C1INH preserved lung structure in animal models. Nuijens teach the C1 inhibitor (C1INH) with shorter half-life than plasma-derived C1 inhibitor for the preparation of a medicament for the treatment of an individual with ARDS. Nuijens provides therapeutically effective amounts of C1INH, routes of administration, as well as guidance for assessing treatment. Elshabrawy et al and Gorbalenya et al teach that SARS-CoV/ SARS-CoV-2 infection cause ARDS. It would have been obvious to the skilled artisan to administer a therapeutically effective amount of C1INH to a patient suffering from ARDS related to a SARS-CoV-2 infection. No more than routine skill is required to administer the well-known dosage routine for C1INH. The benefit of combining references would be a better method of treating and preventing damage by the ARDS to lungs, as taught by Wygrecka et al. Furthermore, the limitations every eight or twelve hours, for a period of at least 72 or 96 hours, this would be considered optimization of experimental parameters and would be obvious to one of ordinary skill in the art, especially when the prior art taught the well-known dosage scheme for the well-known C1INH. However, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235(CCPA 1955).
Additionally, KSR International Co. v, Teleflex inc., 50 U.S. 398, 82 USPQ2d 1385 (2007) discloses combining prior art elements according to known methods to yield predictable results, thus the combination is obvious unless its application is beyond that person's skill. "The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results". Id. at 415-16, 82 USPQ2d at 1395. The combination would have yielded a reasonable expectation of success along with predictable results to one of ordinary skill in the art at the time of the invention. Thus, it would have been obvious to a person of ordinary skill in the art to combine prior art elements according to known methods that is ready for improvement to yield predictable results. The claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Accordingly, claims 29, 30, and 34-38 are rendered obvious. It is further noted that Riedl provides dosing guidance based on a patient weight of more or less than 84 kg. Nuijens taught assessment of efficacy of treatment and continuation of dosing (Ex 1; pp. 2-4 as previously cited).
Regarding claims 12 and 13, Wygrecka et al. teach that ARDS patients often require ventilators/ventilation (pp. 187, 193-194). Administration of C1INH before or after the patient is on a ventilator is deemed to be routine optimization on the part of the skilled artisan, e.g., medical professional.
Claims 1, 9, 12, 13, 17, 21, 27-30, 34-38, 63 and 64 are rendered obvious in view of the teachings of the cited references.
Response to Arguments
Applicant’s arguments with respect to Nuijens, Nuijens 2, Elshabrawy and Gorbalenya is set forth above. Examiner’s rebuttal arguments are also set forth and incorporated herein.
Applicant further alleges mischaracterization of the references and that Nuijens does not teach dosing frequencies but single dose profiles, weight based doses, and no treatment durations (reply at p. 15). Applicant asserts that Riedl is limited to hereditary angioedema, not respiratory distress, and 48-72 hour window related to an untreated HAE attack (pp. 15-16). Applicant asserts that Wygrecka is a chemical lung injury animal model of a “different etiology” than a coronavirus infection (p. 16).
Applicant asserts that the specific dosing regimens of claims 29, 30, 34-38 are not disclosed by the cited references. Applicant asserts that Nuijens teaches only weight based single doses, no fixed-unit doses, dosing intervals, or treatment durations (reply at p. 16). Applicant further asserts similar arguments for claims 12, 13, 31, 39, and 40. Id.
Examiner has reviewed and considered applicants arguments but is not persuaded.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Contrary to Applicant’s assertion, Nuijens does teach administration of more than one dose of C1INH (Example 1, second screen period and exposure to an escalated dosage). rhC1INH appeared safe and well tolerated also in doses of up to 100 U/kg (para. [033]). Para [0031] indicates human C1INH is administered intravenously at a dose of more than 25, 50 or 70 U/kg body weight of the individual, preferably more than 80, 100, 150 or 200 U/kg body weight of the individual. One unit (U) of C1INH is the amount of C1INH present in 1 millilitre of human blood. One such unit corresponds to approximately 275 microgram plasma derived C1INH. Assuming a molecular weight of 110,000 dalton, the concentration in human plasma of C1INH is 2.5 micromol per litre. Examiner expressly notes that Nuijens [applicant’s own work] teaches: The effective dose, i.e. effective concentration and frequency, will depend on the specific pharmaceutical composition which is used, the severity of the condition and the general state of the patient's health. In general, the effective dose of a pharmaceutical composition which is based on a C1INH may be found by routine optimization (para. [0027]). The reference further teaches that an initial a high initial dose may be used in treatment, which enhances the likelihood of successful treatment. Id.
Wygrecka et al. teach disclose the use of C1INH2 in treating ARDS (abstract, pp 196-197). Wygrecka teach an animal model of ARDS. As taught by Wygrecka, C1INH rescues mice from bleomycin induced lung injury. The early phase after bleomycin challenge is characterized by histomorphologic and pathophysiologic features similar to human ARDS (p, 187, 3rd col). As taught by Elshabrawy and Gorbalenya, severe acute respiratory coronavirus (SARS-CoV) infection in humans results in acute respiratory distress syndrome (ARDS). This is the same patient population of the instant claims.
Riedl teaches safe and effective FDA approved treatment protocols comprising C1INH (Tables 1-2). Riedl teaches a dosing scheme of 50 U/kg of rhC1-INH up to 84 kg body weight and a fixed dose of 4200 U for patients weighing ≥84 kg was deemed appropriate to restore functional C1-INH levels, as well as two doses every 20 hours (e.g., p. 410, 413, Table 1). Under this dosing scheme, 50U/kg body weight at 84 kg body weight = 4200 U x 2 injections [within 24 hours] = 8400 U.
It is further noted that Nuijens teach an initial dose of 100 U/kg (e.g., Table 2). In someone with a body weight of 84 kg, 100 U/kg equates to an initial dose of 8400 U.
Examiner reiterates that their own work, Nuijens teaches than an effective concentration and dosing frequency [construed as dosing regimen/duration] may be found by routine optimization.
The rejection is maintained for at least these reasons and those previously made of record.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 17, 21, 27, 28, and 64 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 16-30 of copending Application No. 18577708 (hereinafter referred to “the ‘708 application), in view of Elshabrawy et al (PLOS One 7(11): e50366 (2012) – previously cited), Gorbalenya et al (Nat Microbiol 5:536-544 (March 2020) – previously cited), and Nuijens (U.S. 2007/0185011 – previously cited). The rejection is maintained from the office action mailed 2/03/2026, but has been amended to reflect claims filed 7/30/2026.
This is a provisional nonstatutory double patenting rejection.
Claim 16 of the ‘708 application recites a method for treating a patient suffering from neurological symptoms related to a viral infection, the method comprising administering a therapeutically effective amount of a C1 esterase inhibitor (C1INH) to the patient. Claim 18 of the ‘708 application recites wherein the neurological symptoms are related to COVID-19 and/or wherein the viral infection is a coronavirus infection, wherein the coronavirus preferably is SARS-CoV-2.
The claims of the ‘708 application do not explicitly recite that the patient with a coronavirus infection is suffering from respiratory distress.
Elshabrawy et al teach that severe acute respiratory coronavirus (SARS-CoV) infection in humans results in acute respiratory distress syndrome (ARDS) (p. 1). Reemergence of SARS in humans remains a credible health threat because of the animal reservoirs. As of now, there is no effective treatment for SARS. Id. Gorbalenya et al teach that the coronavirus-associated acute respiratory disease (SARS) called coronavirus disease 19 (COVID-19) was caused by a coronavirus termed SARS-CoV-2 (abstract, pp. 536, 542).
Nuijens expressly taught administration of C1INH to treat ARDS (abstract, paras. [0026]-[0029], claims 1, 10).
It would have been obvious to one of ordinary skill the art to administer the C1INH of the ‘708 application to a person with a coronavirus infection suffering from respiratory disease. The skilled artisan would have known from Elshabrawy et al and Gorbalenya et al that a patient with a SARS-CoV infection would likely be suffering from respiratory distress because the coronavirus was the causative agent of severe acute respiratory syndrome (SARS/ARDS). The skilled artisan would have had a reasonable expectation of success because Nuijens expressly taught administration of C1INH to treat ARDS (abstract, paras. [0026]-[0029], claims 1, 10). Claim 21 of the ‘708 application recites wherein the patient is a human and/or wherein the C1INH has an amino acid sequence at least 70% identity to the amino acid sequence of endogenous human C1INH.
Accordingly, claim 1 is rendered obvious.
Regarding claim 17, claim 22 of the ‘708 application recites wherein the C1INH has a plasma half-life of less than six hours.
Regarding claim 21, claim 24 of the ‘708 application recites wherein the C1INH is Ruconest® (recombinant human C1INH).
Regarding claims 27 and 28, claim 26 of the ‘708 application recites wherein the C1INH is administered at a dose of at least about 25 U/kg body weight of the patient, or wherein the C1INH is administered at a dose of at least about 50 U/kg body weight of the patient.
Regarding claim 64, claim 19 of the ‘708 application recites that the patient has antibodies against SAR-CoV-2.
Allowable Subject Matter
Claims 31, 39, and 40 appear to be free of the prior art. The closest prior art to the instant claims are the references taught herein. Although Wygrecka et al. teach administration of C1INH resulted in improved clinical symptoms and a decrease in inflammatory markers- e.g., macrophage inflammatory protein (MIP)-2, tumor necrosis factor (TNF)-α, IL-1ß, and neutrophil chemoattractant (KC) expression on the mRNA and/or protein level. The references do not expressly teach a decrease of clinical symptoms/inflammatory markers by 50% of the initial pathological status or reached normal values.
Claims 31, 39, and 40 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
No claims are allowed.
Claims 1, 9, 12, 13, 17, 21, 27-31, 34-40, 63 and 64 are pending.
Claims 1, 9, 12, 13, 17, 21, 27-30, 34-38, 63 and 64 are rejected.
Claims 31, 39, and 40 are objected.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KRISTINA M HELLMAN whose telephone number is (571)272-2836. The examiner can normally be reached M-F 9:00 am-5:30 pm.
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/KRISTINA M HELLMAN/ Examiner, Art Unit 1654
/JULIE HA/ Primary Examiner, Art Unit 1654
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