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 .
Election/Restrictions
Applicant's election with traverse of Species A (i.e., human plasma derived C1 esterase inhibitors as a group as a single and specific C1INH) and Species C (i.e., kidney with risk for delayed graft function and a kidney allograft having a KDPI of 80% or greater as a single and specific allograft) in the reply filed on March 26, 2026, is acknowledged. The traversal for Species A is on the grounds that human plasma derived esterase inhibitors as a group does not appear to be patentably distinct (See Applicant’s Response received on 3/26/26, pg. 6), and the traversal for Species C is on the grounds that the features that may be considered to render a recipient at high risk for DGF if offered a donor allograft with (1) KDPI of 80% or greater, (2) donor after cardiac death status, (3) cold ischemia time >=24 hours, or (4) acute kidney injury with terminal creatinine >=3.0 mg/dL or requiring dialysis are not mutually exclusive. These arguments are not found persuasive because whether the species are patentably distinct or mutually exclusive are not criteria for election/restriction purposes under 35 USC §121 and 35 USC § 372. As indicated in the Restriction mailed on 12/29/25, the Species lack unity of invention in view of WO 2019/055763 A1 (cited in the IDS received on 6/14/23). Therefore, for the reasons stated in the Restriction, Species A and C lack unity of invention.
The requirement is still deemed proper and is therefore made FINAL.
However, please note that Species C is expanded to include where the KDPI is 85% or greater in light of the Examiner’s search. As such, claim 21 is rejoined and examined on the merits.
Applicant’s election without traverse of Species B (i.e., C1INH with saline and heparin as a single and specific combination of agents and/or therapies; and intrarenal administration of heparinized saline, followed by one intrarenal dose of C1INH at about 500 U/kidney about 1-2 hours before implantation and reperfusion of the allograft as the single and specific dosing regimen) in the reply filed on March 26, 2026, is acknowledged.
Status of Claims
Claims 1-28 were originally filed on June 14, 2023.
The amendment received on June 14, 2023, canceled claims 4-7, 14, 16, 18, and 28; and amended claims 3, 8-11, 13, 15, 17, 19-20, and 27. The amendment received on March 26, 2026, amended claim 10.
Claims 1-3, 8-13, 15, 17, and 19-27 are currently pending and claims 1-2, 9-13, and 19-21 are under consideration as claims 22-26 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on March 26, 2026. Claims 3, 8, 15, 17, and 27 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on March 26, 2026.
Priority
The present application claims status as a 371 (National Stage) of PCT/US21/64678 filed December 21, 2021, and claims priority under 119(e) to U.S. Provisional Application No. 63/128,757 filed on December 21, 2020.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on June 14, 2023; September 14, 2023; and March 26, 2026, are being considered by the examiner.
Please note that document FP4 cited in the IDS received on 6/14/23, i.e., EP 1240904, has been crossed out and not considered because an English language translation, abstract, or statement of relevance has not been provided pursuant to 37 CFR 1.98.
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 1-2, 9-13, and 19-21 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Independent claim 1 includes administration of “a complement component 1 esterase inhibitor (C1-INH)”. Dependent claim 10 includes where the C1-INH is a human plasma-derived C1 esterase inhibitor. The instant specification defines a C1-INH as referring to the proteins or fragments thereof that function as serine protease inhibitors to inhibit proteases associated with the complement system, with the kallikrein-kinin system, and with the coagulation system (See instant, [0011]). Plus, C1-INH 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 (See instant, [0011]). The human C1-INH protein is 500 amino acids in length including a 22 amino acid signal peptide sequence (See instant, [0011]). As such, the claimed C1-INH in claim 1 encompasses full length wild-type proteins, any fragment thereof including a fragment with a single deleted residue at the N- or C-terminus up to any dipeptide (i.e., any two contiguous residues), and any peptide mimetic of a wild-type C1-INH protein. It is noted that the instant specification does not define what constitutes a C1-INH peptide mimetic. As such, the plain and ordinary meaning of the term applies. The term, peptide mimetics, has been used for the description of compounds discovered through a variety of research strategies including a peptide, a modified peptide or any other molecules that biologically mimics active ligands of hormones, cytokines, enzyme substrates, viruses or other biomolecules (See BioSynthesis, “Peptide Mimetics”, available online at https://www.biosyn.com/tew/peptide-mimetics.aspx, 7 pages (2012) at pg. 1, 2nd paragraph). As such, a peptide mimetic of C1-INH includes any peptide, modified peptide, or any other molecule such as a small molecule, saccharide, etc., that will mimic the function of serine protease inhibitors to inhibit proteases associated with the complement system, with the kallikrein-kinin system, and with the coagulation system. Moreover, when the C1-INH is a human plasma-derived C1-INH, the C1-INH encompasses any human C1-INH protein, any fragment thereof including a fragment with a single deleted residue at the N- or C-terminus up to any dipeptide (i.e., any two contiguous residues), any modified C1-INH protein including variants or analogues such as Ruconest®. Therefore, the claimed C1-INH encompasses a vast array of molecules without a core structure or sequence necessary to exhibit the function of serine protease inhibitors to inhibit proteases associated with the complement system, with the kallikrein-kinin system, and with the coagulation system.
The written description requirement may be met by provided a representative number of species of the genus and/or in light of the state of the art. With regard to the state of the art, Mannesse et al. teaches a naturally occurring plasma derived C1-INH and a recombinant preparation of C1-INH (See Mannesse WO 2007/073186 A2 published on June 28, 2007 at pg. 2, 2nd paragraph). A known difference between the naturally occurring plasma derived C1-INH and the recombinant C1-INH preparation is the extent and type of glycosylation (See Mannesse, pg. 2, 3rd paragraph). The recombinant glycoprotein contains a broad array of different N-glycans comprising oligomannose-, hybrid-, and complex-type structures, whereas the N-glycans of plasma derived C1-INH are mainly composed of fully sialylated complex-type structures (See Mannesse, pg. 2, 3rd paragraph). The glycosylation structure difference affects the half-life of both C1-INH (See Mannesse, pg. 2, 3rd paragraph). The C1-INH amino acid sequence comprises the mature human C1-INH of SEQ ID NO: 1 (See Mannesse, pg. 3, 1st paragraph). The C1-INH preparation is obtained from the milk of transgenic rabbits (See Mannesse, pg. 4, 3rd paragraph). It can have a modified carbohydrate structure compared to the plasma derived C1-INH (See Mannesse, pg. 5, 1st to pg. 6, 1st paragraph). Furthermore, Fuessner et al. compared four commercially available C1-INH proteins; namely, Ruconest®, Berinert®, Cetor®, and Cinryze® (See Fuessner et al., Transfusion 54:2566-2573 (2014) at abstract). Ruconest® is an analogue of the human C1-INH protein that is purified from the milk of rabbits (See Fuessner, pg. 2568, col. 1, 3rd paragraph). Berinert®, Cetor®, and Cinryze® are derived from human plasma and differ in purification and steps but have the same C1-INH amino acid sequence (See Fuessner, pg. 2567, col. 2, last paragraph). As such, the state of the art supports specific species of C1-INHs. However, the state of the art does not indicate a core structure or sequence necessary for a protein, peptide, peptide mimetic, or fragment to function of serine protease inhibitors to inhibit proteases associated with the complement system, with the kallikrein-kinin system, and with the coagulation system. Thus, the claims are directed to C1-INH molecules with a certain function but no correlated structure associated with that function. Without such structure, the specification does not convey possession of the breadth of the claimed genus.
Alternatively, the written description requirement may be met by provided a representative number of species of the genus. In this, the specification teaches three specific species of C1-INHs; more specifically Berinert®, and Cinryze®, or Ruconest® (See instant, [0012], [0025]-[0030]). Berinert® and Cinryze® are each derived from human plasma but obtained and purified via different methods (See instant, [0026], [0028]). Ruconest® is a recombinant analogue of human C1-INH, and is purified from the milk of transgenic rabbits (See instant, [0027]). The specification also teaches that the C1-INH can have an amino acid sequence that has at least 65% identity with the human C1-INH amino acid sequence (See instant, [0033]). However, no specific examples are provided that would indicate a core structure and/or sequence needed for an amino acid sequence that is at least 65% identical to the human C1-INH amino acid sequence to inhibit proteases associated with the complement system, with the kallikrein-kinin system, and with the coagulation system. Plus, the disclosure of three species of C1-INH is insufficient to constitute a representative number of C1-INHs, especially given the breadth of the claimed genus that includes any C1-INH protein, any fragment of any length thereof, and any peptide mimetic of C1-INH. Thus, the specification is not sufficient for the skilled artisan to envisage which C1-INHs will preserve function other than the natural occurring human C1-INH and one C1-INH analogue having a modified glycosylation pattern.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, what is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116). As discussed above, the skilled artisan cannot envision the detailed chemical structure of the encompassed genus of polypeptides which preserve the required function, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence. Therefore, claims 1-2, 9-13, and 19-21 do not meet the written description requirement.
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 1-2, 9-13, and 19-21 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. The term “long-term” in claim 1 is a relative term which renders the claim indefinite as it is unclear what time frame “long-term” refers to. The term “long-term” in relation to improving graft function is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Please note that claims 2, 9-13, and 19-20 are rejected by virtue of their dependency.
Claim 9 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 9 recites the limitation "the renal artery" in lines 2-3. It is noted that claim 9 is dependent upon claim 1, which does not limit the allograft to a kidney. As such, claim 1 encompasses any allograft, which do not per se contain a renal artery. Thus, there is insufficient antecedent basis for this limitation in the claim.
Please note that the Examiner is interpreting the scope of claim 9 such that it is dependent upon claim 19 in order to advance prosecution.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 10, and 19 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Jordan et al. WO 2019/055763 A1 published on March 21, 2019 (cited in the IDS received on 6/14/23).
For claims 1 and 19, Jordan claims a method for improving graft kidney function or reducing the likelihood of or treating delayed kidney function in a subject that will undergo kidney transplant comprising administering ex vivo to the kidney to be transplanted a therapeutically effective amount of one or more C1-INHs (See Jordan, claim 18; [0046]). Jordan defines “treating” as where the object is to prevent, reverse, alleviate, ameliorate, inhibit, lessen, slow down or stop the progression or severity of a symptom or condition (See Jordan, [0033]). The term “treating” includes reducing or alleviating at least one adverse effect or symptom of a condition (See Jordan, [0033]). As such, treating delayed kidney function includes slowing down, or reducing at least one adverse effect or symptom of delayed graft function. Thus, Jordan’s method for improving graft kidney function or reducing the likelihood of or treating delayed kidney function constitutes the instant method of reducing delayed graft function where delayed kidney function is a species of a delayed graft function and where treating delayed kidney function would necessarily result in its reduction.
Moreover, Jordan’s administering a therapeutically effective amount of at least one C1-INH constitutes the instant administering of a therapeutically effective dose of C1-INH. Plus, Jordan’s administering the therapeutically effective amount of at least one C1-INH ex vivo to a kidney to be transplanted to a subject constitutes the instant administration of the C1-INH to an allograft where the allograft is a kidney prior to implantation of the kidney into the subject. Thus, Jordan’s claim 18 satisfies the claim limitations as recited in instant claims 1 and 19.
For claim 10, Jordan discloses that exemplary C1-INHs include a purified C1-INH from human blood (Cinryze®), a recombinant analogue of human C1-INH (Ruconest®), a recombinant human C1-INH produced in the milk of transgenic rabbits (Rhucin®), and a human plasma-derived, purified, pasteurized, lyophilized concentrate of C1-INH (Berinert®) (See Jordan, [0011], [0046]). Example 1 administers Berinert® intraoperatively (See Jordan, [0063]) thereby constituting a specific embodiment. Pursuant to MPEP 2131.02, it states that, “[i]f one of ordinary skill in the art is able to "at once envisage" the specific compound within the generic chemical formula, the compound is anticipated. One of ordinary skill in the art must be able to draw the structural formula or write the name of each of the compounds included in the generic formula before any of the compounds can be "at once envisaged." One may look to the preferred embodiments to determine which compounds can be anticipated.” In re Petering, 301 F.2d 676, 133 USPQ 275 (CCPA 1962). Although Jordan’s claim 18 does not expressly claim that the administered C1-INH is a human plasma-derived C1-INH, since Jordan discloses four species of C1-INHs as the C1-INH to be administered, an ordinary skilled artisan would “at once envisage” that the C1-INH is a human plasma-derived C1-INH, i.e., Berinert®. Thus, Jordan’s disclosure satisfies the claim limitation with respect to where the C1-INH is a human plasma-derived C1-INH as recited in instant claim 10.
Accordingly, Jordan’s disclosure anticipates instant claims 1, 10, and 19.
Claim Rejections - 35 USC § 103
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) 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 under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
103 - KSR Examples of 'Rationales' Supporting a Conclusion of Obviousness(Consistent with the "Functional Approach" of Graham)
Further regarding 35 USC 103(a) rejections, the Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 127 S. Ct. 1727, 82 USPQ2d 1385, 1395-97 (2007) (KSR) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit.
Exemplary rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Note that the list of rationales provided is not intended to be an all-inclusive list. Other rationales to support a conclusion of obviousness may be relied upon by Office personnel.
Also, a reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976).
Claims 11-13 and 20-21 are rejected under 35 U.S.C. 103 as being unpatentable over Jordan et al. WO 2019/055763 A1 published on March 21, 2019 (cited in the IDS received on 6/14/23), as applied to claim 1 above, and as applied to claims 11-13 and 20-21 herewith.
For claims 11-12, with respect to the therapeutically effective dose of C1-INH:
Jordan et al. teaches that typical dosages of an effective amount of one or more C1-INHs can be in the ranges recommended by the manufacturer where known therapeutic compounds are used, and also as indicated to the skilled artisan by the in vitro responses or responses in animal models (See Jordan, [0060]). For example, Jordan et al. teaches that Berinert® is currently recommended at 50 U/kg (rounded to the nearest 500 Units) intravenously (See Jordan, [0060]). Since Jordan et al. teaches administering the C1-INH such as Berinert® to a kidney prior to implantation thereby constituting direct administration to the kidney (i.e., allograft), it would then follow that Jordan suggests administering about 500 Units of Berinert® per kidney given that about 500 Units is the recommended therapeutically effective amount.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application to administer about 500 Units of Berinert® to a kidney prior to implantation into a subject in order to reduce delayed kidney function. One of ordinary skill in the art at the time the invention was made would have been motivated to do so because a therapeutically effective dose of Berinert® was known to be recommended at about 500 Units (i.e., 50 Units/kg) as taught by Jordan et al. One of ordinary skill in the art at the time the invention was made would have had a reasonable expectation of success given that a therapeutically effective amount of Berinert® of Jordan et al. was administered to a kidney prior to implantation into a subject, and therefore, administering about 500 Units of Berinert® as the therapeutically effective amount to the kidney prior to implantation into a subject would support the reduction of delayed kidney function by constituting some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant to KSR.
Additionally, it is noted that the amount of Berinert® being about 500 Units per kidney lies inside the claimed range of about 250-1000 Units/allograft as recited in instant claim 11. MPEP 2144.05(I) states that "[i]n the case where the claimed ranges "overlap or lie inside ranges discloses by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) (The prior art taught carbon monoxide concentrations of "about 1-5%" while the claim was limited to "more than 5%". The court held that "about 1-5%" allowed for concentrations slightly above 5% thus the ranges overlapped.) Moreover, the Federal Circuit found that a prima facie case existed where a claim reciting thickness of a protective layer as falling within a range of "50 to 100 Angstroms and the prior art taught that "for suitable protection, the thickness of the protective layer should be not less than about 10 nm [i.e., 100 Angstroms]." In re Geisler, 116 F.3d 1465, 1469-82, 43 USPQ2d 1362, 1365-66 (Fed. Cir. 1997). Therefore, the claimed therapeutically effective dose range of C1-INH would have been obvious to one of ordinary skill in the art since the claimed range (i.e., about 250-1000 Units/allograft) overlaps with the prior art therapeutically effective dose of C1-INH (i.e., about 500 Units per kidney).
For claim 13, with respect to the timeframe the C1-INH is administered to the kidney prior to implantation:
As discussed supra for claim 1, Jordan et al. claims administering a therapeutically effective dose of a C1-INH to a kidney prior to implantation into a subject in order to reduce delayed kidney function. Jordan et al. also teaches that the organ to be transplanted can be treated with an effective amount of C1-INHs at the time of procurement from the donor, about 36-30 hours, about 30-25 hours….about 5-1 hour or combinations thereof prior to implantation of the organ in the subject (See Jordan, [0052]). Jordan et al. further teaches that in some embodiments, the organ is treated with an effective amount of C1-INHs about 1 hour, 2 hours, etc. prior to implantation of the organ in the subject (See Jordan, [0052]). Therefore, the teachings of Jordan et al. suggest administering a therapeutically effective amount of Berinert® to a kidney about 1-2 hours prior to implantation into a subject.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application to administer Berinert® to an allograft such as a kidney about 1-2 hours prior to implantation into a subject in order to reduce delayed kidney function. One of ordinary skill in the art at the time the invention was made would have been motivated to do so because an allograft such as a kidney was known to be treated with an effective amount of Berinert® 1-24 hours prior to implantation into a subject as taught by Jordan et al. One of ordinary skill in the art at the time the invention was made would have had a reasonable expectation of success given that an allograft such as a kidney of Jordan et al. was treated with a C1-INH such as Berinert® to the allograft prior to implantation into a subject, and therefore, treating the allograft about 1-2 hours prior to implantation into a subject would support the reduction of delayed kidney function by constituting some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant to KSR.
Additionally, it is noted that the timeframe the C1-INH is administered to the kidney prior to implantation taught by Jordan et al. overlaps with the claimed timeframe range of about 1-2 hours as recited in instant claim 13. MPEP 2144.05(I) states that "[i]n the case where the claimed ranges "overlap or lie inside ranges discloses by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) (The prior art taught carbon monoxide concentrations of "about 1-5%" while the claim was limited to "more than 5%". The court held that "about 1-5%" allowed for concentrations slightly above 5% thus the ranges overlapped.) Moreover, the Federal Circuit found that a prima facie case existed where a claim reciting thickness of a protective layer as falling within a range of "50 to 100 Angstroms and the prior art taught that "for suitable protection, the thickness of the protective layer should be not less than about 10 nm [i.e., 100 Angstroms]." In re Geisler, 116 F.3d 1465, 1469-82, 43 USPQ2d 1362, 1365-66 (Fed. Cir. 1997). Therefore, the claimed timeframe at which the C1-INH is administered to the allograft prior to implantation into a subject would have been obvious to one of ordinary skill in the art since the claimed range (i.e., about 1-2 hours) overlaps with the prior art timeframe range (i.e., about 1-24 hours).
For claims 20-21, with respect to where the kidney is a kidney allograft having a kidney donor profile index (KDPI) of 80% or 85% or greater:
Jordan et al. teaches that the DDPI is predictive of delayed graft function and risk of allograft loss (See Jordan, [0088]). A KDPI >85% confers the highest risk (See Jordan, [0088]). In Example 2, Jordan et al. examined the protective effect of Berinert® administration against ischemia reperfusion injury (IRI) and delayed graft function in patients receiving a kidney transplant (See Jordan, [0073]). Jordan et al. teaches that the donor kidney includes kidneys with a KDPI of >85% (See Jordan, [0088], Table 2). C1-INH administration resulted in transplant recipients needing less dialysis when transplanting a kidney with a KDPI of >85% (See Jordan, [0092]). Thus, the teachings of Jordan et al. suggest reducing delayed kidney function for a subject transplanted with a kidney that has a KDPI of >85% by administering a therapeutically effective amount of a C1-INH.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application to administer Berinert® to an allograft such as a kidney with a KDPI of >85% prior to implantation into a subject in order to reduce delayed kidney function. One of ordinary skill in the art at the time the invention was made would have been motivated to do so because administering a C1-INH was known to reduce delayed kidney function when transplanting a kidney with a KDPI of >85% into a subject by reducing the need for dialysis as taught by Jordan et al. One of ordinary skill in the art at the time the invention was made would have had a reasonable expectation of success given that a therapeutically effective amount of Berinert® of Jordan et al. was administered to a kidney prior to implantation into a subject, and therefore, administering the therapeutically effective amount of Berinert® to a kidney with a KDPI >85% prior to implantation into a subject would support the reduction of delayed kidney function by constituting some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant to KSR.
Additionally, it is noted that the KDPI percent taught by Jordan et al. overlaps with the claimed KDPI percent range of 80% or greater as recited in instant claim 20. MPEP 2144.05(I) states that "[i]n the case where the claimed ranges "overlap or lie inside ranges discloses by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) (The prior art taught carbon monoxide concentrations of "about 1-5%" while the claim was limited to "more than 5%". The court held that "about 1-5%" allowed for concentrations slightly above 5% thus the ranges overlapped.) Moreover, the Federal Circuit found that a prima facie case existed where a claim reciting thickness of a protective layer as falling within a range of "50 to 100 Angstroms and the prior art taught that "for suitable protection, the thickness of the protective layer should be not less than about 10 nm [i.e., 100 Angstroms]." In re Geisler, 116 F.3d 1465, 1469-82, 43 USPQ2d 1362, 1365-66 (Fed. Cir. 1997). Therefore, the claimed KDPI percentage of the kidney to be transplanted would have been obvious to one of ordinary skill in the art since the claimed KDPI percent range (i.e., 80% or greater) overlaps with the prior art KDPI percent range (i.e., 85% or greater).
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Jordan et al. WO 2019/055763 A1 published on March 21, 2019 (cited in the IDS received on 6/14/23), as applied to claim 1 above, and further in view of Kron et al., Transplantation 103:e128-e136 (2019), and Amos, J., “Protective organ wash engineered,” available online at www.bbc.com/news/science-environment-11322197#:~:text=Mr%20Martin%20Drage%2C%20a%20consultant,kidney%20on%20ice%20and%20transport, 7 pages (2010), as applied to claim 2 herewith.
For claim 2, with respect to where heparinized saline is administered to the allograft prior to administering the therapeutically effective dose of C1-INH:
Jordan et al. identified the donor and transplant characteristics in Table 2 (See Jordan, [0089]; Table 2). Plus, as discussed supra for claim 13, Jordan et al. teaches that the C1-INH can be administered to the kidney about 1-24 hours prior to implantation. However, Jordan et al. does not expressly teach or suggest the procedure/protocol for procuring the kidney from the donor and preserving it prior to implantation into the donor recipient.
Kron et al. teaches that donor kidneys are flushed in situ with 6 ml heparinized (1 U/ml) saline at room temperature via aorta (renal artery) (See Kron, pg. e130, col. 2, 2nd paragraph). Kidneys were then excised and placed in precooled UW solution (4°C) (See Kron, pg. e130, col. 2, 2nd paragraph). It is noted that the scope of claim 2 only requires that the saline (i.e., heparinized saline as elected) is administered to the allograft before the C1-INH is administered to it. Since Jordan et al. teaches that the C1-INH can be administered to the kidney 1-24 hours prior to implantation, and Kron et al. teaches that donor kidneys are flushed with heparinized saline before excision, it would then follow that heparinized saline is administered to the kidney prior to C1-INH administration.
Amos teaches that a donor kidney should be flushed in order to remove the blood because it could clot and destroy the kidney before you put the kidney on ice and transport (See Amos, pg. 3, 11 paragraph).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application to administer heparinized saline to a donor kidney prior to administration of C1-INH in order to flush the blood from the donor kidney thereby reducing potential for clotting that could destroy the kidney before you put the kidney on ice and transport. One of ordinary skill in the art at the time the invention was made would have been motivated to do so because a donor kidney was known to be flushed with heparinized saline prior to excision as taught by Kron et al.; and because flushing a donor kidney was known to remove the blood because it could clot and destroy the kidney before you put the kidney on ice and transport as taught by Amos. One of ordinary skill in the art at the time the invention was made would have had a reasonable expectation of success given that the donor kidney of Jordan et al. was administered a therapeutically effective dose of Berinert® about 1-24 hours prior to implantation into a subject, and therefore, administering heparinized saline to the donor kidney prior to C1-INH administration would support the reduced incidence of clotting thereby destroying the donor kidney by constituting some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention and/or the use of a known technique to improve similar devices (methods, or products) in the same way and/or the application of a known technique to a known device (method, or product) ready for improvement to yield predictable results pursuant to KSR.
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Jordan et al. WO 2019/055763 A1 published on March 21, 2019 (cited in the IDS received on 6/14/23), as applied to claim 1 above, and further in view of Krishna et al., J. Clin. Nephrol. Ren. Care 6:9 pages (December 4th, 2020), as applied to claim 9 herewith.
For claim 9, with respect to where the C1-INH is infused into the renal artery:
As discussed supra for claim 1, Jordan et al. teaches administering a therapeutically effective dose of a C1-INH to a donor kidney prior to implantation into a subject. Jordan et al. also defines “administering” as referring to the placement of an agent or a composition as disclosed herein into a subject by a method or route which results in at least partial localization of the agents or composition at a desired site (See Jordan, [0039]). The route of administration includes parenteral administration such as intraarterial (See Jordan, [0039]). The composition can be in the form of solutions or suspensions for infusion or for injection (See Jordan, [0039]). Jordan et al. further teaches that the C1-INH composition can be administered to the donor kidney about 1-24 hours prior to implantation. However, Jordan et al. does not expressly teach or suggest where the C1-INH is administered to the donor kidney by infusion int the renal artery.
Krishna et al. performed a retrospective comparative analysis of a prospectively maintained database of all the patients undergoing live related renal allograft transplant from January 2015 till December 2019 (See Krishna, abstract). There were 422 eligible transplant patients out of which 92 (21.8%) patients had grafts with complex vascular anatomy and 330 (78.2%) patients had single renal artery and vein (See Krishna, abstract, pg. 3, col. 2, last paragraph to pg. 4, col. 1, 1st paragraph; Figure 1). Of the 92 patients with complex vascular anatomy, 62 patients had double arteries and 30 had triple arteries (See Krishna, Table 1). Most of the patients with complex vascular anatomy had a main renal artery and an accessory renal artery (58.6%) and the remaining had either an upper or lower polar artery (See Krishna, pg. 4, col. 1, 2nd paragraph). Double renal vein was seen in 17 patients (See Krishna, pg. 4, col. 1, 2nd paragraph). Thus, Krishna et al. demonstrates that a donor kidney has a finite number of points of administration, i.e., 1-3 arteries and 1-2 veins.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application to infuse Berinert® in the form of a solution or suspension into a renal artery of to a donor kidney prior to implantation into a subject in order to reduce delayed kidney function. One of ordinary skill in the art at the time the invention was made would have been motivated to do so because a donor kidney was known to have 1-3 arteries and 1-2 veins where the majority of donor kidneys had 1 renal artery and 1 renal vein as taught by Krishna et al. As such, a donor kidney thereby constituting a finite number of administration routes when administering C1-INH to a donor kidney prior to implantation into a subject. These routes include infusion/injection into a renal artery or a renal vein, injection into the kidney tissue, or topical administration. In light of the finite number of administration routes and administration sites, one of ordinary skill in the art at the time the invention was made would have had a reasonable expectation of success to try given that a therapeutically effective amount of Berinert® of Jordan et al. was administered to a donor kidney prior to implantation into a subject and was formulated as a solution or suspension for infusion or injection intraarterially, and therefore, administering the therapeutically effective amount of Berinert® via infusion to a renal artery would support the reduction of delayed kidney function by constituting an "Obvious to try" rationale - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success and/or some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant to KSR.
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Conclusion
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/THEA D' AMBROSIO/Primary Examiner, Art Unit 1654
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