DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant's election without traverse of Invention group II, drawn to a kidney isolated from a miniature swine, wherein the glomeruli of the kidney express human CD47 at a level higher than the level of human CD47 in the tubules of the kidney.
Claims 23, 25-26, 29-30 in the reply filed on 12/23/2025 is acknowledged. Claims 56-80 are newly added and will be considered with the claims of elected group II.
Claims 1-13, 22 , 32-33, 37, 40-41, 46, 49, 51, 52, 55 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species/invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 12/23/2025.
Claim status
Claims 23, 25-26, 29-30, 56-80 are pending.
Claims 1-22, 24, 27-28, 31-55, are cancelled.
Claims 23, 25-26, 29-30, 56-80 are under examination.
Claim objections
Claims 61 and 68 are objected to in the recitation of “glomerulus-specific promoter is nephrin”, and in the interest of improving claim form, it is suggested that the recited phrase be amended to recite “glomerulus-specific promoter is a nephrin promoter”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 26 and 66 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claims 26 and 66 are dependent on the claims 23 and 64 which recite the limitation of glomeruli expression of hCD47, at a level higher than the level of hCD47 expression in the tubules of the kidney. Claims 26, and 66 recite the limitation of expression of hCD47 under the same regulatory elements as the endogenous porcine CD47. However, the endogenous CD47 is a ubiquitously expressed cell surface glycoprotein as evidenced by Tena (introduction, page 2714). Therefore, it is not clear how the expression of hCD47 under the endogenous porcine CD47 could lead to higher expression of it in the glomeruli compared to the tubules of the kidney. Therefore, the dependent claims fail to further limit the claims upon which they depend and fail to include all the limitations of the independent claims.
Applicant may cancel the claims, amend the claims to place the claims in proper dependent form, rewrite the claims in independent form, or present a sufficient showing that the dependent claims comply with the statutory requirements.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 23, 25,29, 30, 60-62 are rejected under 35 U.S.C. 103 as being unpatentable over Yamada, Kazuhiko, et al., Nature medicine 11.1 (2005): 32-34, in view of Tena, Aseda, et al., " American Journal of transplantation 14.12 (2014): 2713-2722, Wong, M. Andrew, et al, American Journal of Physiology-Renal Physiology 279.6 (2000): F1027-F1032, and El‐Rashid, Maryam, et al., The FASEB Journal 33.11 (2019): 12735-12749.
Regarding claim 23, Yamada teaches α-1,3-galactosyltransferase knock out (GalTKO-KO) miniature swine kidneys grafted into baboon recipients (page 33, paragraph 2, fig. 1a) which led to increase in renal xenograft survival time from 30 to over 80 days.
Yamada does not teach a miniature swine kidney that expresses higher level of human CD47 (hCD47) in glomeruli than in the tubules of the kidney.
Tena teaches the generation of human hCD47 bearing transgenic miniature swine (page 2714, materials and methods, animals, vector construction and fibroblast transfection/selection and pig cloning), that has wide spread expression of hCD47 in all three germ layers of animals (figure 4D, page 2718), indicating hCD47 expression in kidneys which is derived from the mesoderm. Tena also teaches that the expression of hCD47 on porcine cells inhibit phagocytosis by human macrophages which is achieved through inhibition of the signal regulatory protein- α expressed on macrophages, resulting in increased engraftment success due to evasion of macrophage attack (Introduction, paragraph 2, page 2714).
Tena does not teach a miniature swine kidney that expresses higher level of hCD47 in glomeruli than in the tubules of the kidney.
Wong teaches a glomerular specific promoter from the human nephrin gene Nephrin is expressed in podocytes which are highly specialized cells that make up the glomerular filtration barrier in kidney. Wong et al. have identified a 1.25 kb DNA fragment from the human nephrin promoter and a 5’-flanking region that enables podocyte specific expression of genes that result in glomerular specific expression (abstract, page F1027).
Wong does not teach the high glomerular expression of CD47 compared to its’ expression level in kidney tubules.
El‐Rashid teaches that activated CD47 promotes acute kidney injury (AKI) through inhibition of autophagy (abstract, page 12735). AKI is tied to renal tubular epithelial cell (RTEC) death, causing tubular inflammation, vasoconstriction and manifesting as renal dysfunction. A high level of constitutive autophagy is observed in RTEC where it is needed to maintain the general health of RTEC (introduction, paragraph 2, page 12735). CD47 signaling reduces autophagy which results in increased RTEC death and thereby increased risk of AKI ( CD47 limits expression of autophagy in RTECs to promote cell death, page 12743). Therefore, expressing hCD47 at lower levels in the kidney tubules will provide protection to tubules from RTEC death, and thereby from AKI.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to modify the above mentioned teachings of Yamada that teaches GalTKO miniature swine kidneys, with Tena that teaches the generation of human CD47 (hCD47) bearing transgenic miniature swine, Wong that teaches a glomerular specific promoter from the human nephrin gene, and El‐Rashid that teaches CD47 mediated acute kidney injury (AKI) through inhibition of renal tubular autophagy to result in low expression of hCD47 in tubules. One of ordinary skill in the art would have been motivated to combine the teachings of Yamada, Tena, Wong, and El-Rashid to produce a miniature swine kidney that expresses hCD47 in glomeruli at a level higher than the level of hCD47 in tubules to prevent phagocytosis by macrophages in glomeruli, and to prevent AKI . There would be reasonable expectation of success to combine the teachings of Yamada, Tena, Wong, and El-Rashid, because, Yamada teaches the survival of their kidney in baboons for over 80 days, Tena teaches the evasion of phagocytosis by macrophages by the expression of hCD47, Wong teaches a glomerular specific promotor that can be used to elevate the expression of hCD47 in glomeruli at a level higher than its’ expression in the kidney tubules to prevent RTEC death associated AKI as taught by El-Rashid.
Regarding claims 26 and 66, in light of the 112d rejection, claims 26 and 66 are interpreted to read on a glomeruli specific promoter.
Regarding claim 29, Yamada teaches a miniature swine thymokidney ( fig. 1a, table 1, pages 33 and 34).
Regarding claim 30, Yamada teaches α-1,3-galactosyltransferase knock out (GalTKO) miniature swine kidneys grafted into baboon recipients (page 33, paragraph 2, fig. 1a).
Regarding claim 25, Tena teaches the measuring of hCD47 expression level by real-time PCR (page 2718, fig. 4D).
Regarding claims 56-59, Wong teaches a glomerular specific promoter from the human nephrin gene. Wherein, the nephrin is expressed in podocytes which are highly specialized cells that make up the glomerular filtration barrier in kidney.
Tena teaches the generation of hCD47 bearing transgenic miniature swine.
Expression of hCD47 under the nephrin promoter will lead to glomerular specific expression of hCD47 at a level higher than its’ expression in the kidney tubules. The high levels of glomerular expression which is 2-10 times, at least 100 times, 2 to 50 times, and 51-100 times higher than that of kidney tubules can be achieved by expressing hCD47 under the glomerular specific, nephrin promoter, as taught by Wong.
Regarding claim 60 and 61, Wong teaches a glomerular specific promoter from the human nephrin gene. Wherein, the nephrin is expressed in podocytes which are highly specialized cells that make up the glomerular filtration barrier in kidney.
Tena teaches the generation of human CD47 (hCD47) bearing transgenic miniature swine.
Therefore, expression of hCD47 under the glomerulus-specific nephrin promoter would result in a miniature swine kidney that express hCD47 in glomeruli.
Regarding claim 62, Tena teaches GalTkO deficient, MHC-inbred Columbia/Sachs miniature swine, as evidenced by Watanabe et al. 2021 (animal donors, page 3) and Tena et al. 2017.
Hence, the claimed invention as a whole was prima facie obvious.
Claims 63-80 are rejected under 35 U.S.C. 103 as being unpatentable over Yamada, Kazuhiko, et al., Tena, Aseda, et al, Wong, M. Andrew et al., and El-Rashid et al. as applied to claims 23, 25,29, 30, 60-62 above, and further in view of Nomura, Shunichiro, et al., Transplantation 102 (2018): S314-S315.
Teachings of Yamada, Tena, Wong and El-Rashid are as relied on above.
Yamada, Tena and Wong do not teach the glomerular expression of CD47 at levels sufficient to reduce protein excretion to less than 150mg per day or to prevent or reduce the proteinuria in a kidney transplant recipient.
Regarding claims 63 and 72, Nomura teaches the glomerular expression of hCD47 at levels sufficient to reduce proteinuria (i.e. protein excretion via urine) less than 150mg per day. The mean proteinuria/10 days were ≤ 100mg/dL for the first hundred days after hCD47 positive kidney xenograft from porcine to baboon from both kidneys that showed high and low expression of hCD47 prior to transplant (fig 1, A-3 , and fig.2, page S314), and 0mg/dL on 31-40 days and 61-70 days after xenograft in hCD47 high expression porcine kidneys (fig. 1 A-3, page S314). The level of proteinuria was higher in their negative control groups, ex: GalTKO kidneys from swine without hCD47 expression.
Regarding claim 64, Nomura teaches the glomerular expression of hCD47 at levels sufficient to prevent or reduce the severity proteinuria in a kidney transplant recipient compared to hCD47 negative kidney recipients (GalTKO alone) (fig. 1 A-1, A-3, page S314).
Regarding claim 73, Nomura teaches about 70% reduction in proteinuria in hCD47 positive and GalTKO kidney recipients compared to the control GalTKO kidney recipients at 11-20 days after transplant (fig. 1 A-1, A-3, page S314).
Regarding claim 74, Nomura teaches expression of hCD47 at levels sufficient to prevent or reduce the duration of proteinuria. The control animals who received GalTKO kidneys were euthanized due to development of massive proteinuria at 70 days post operation, while hCD47 high +GalTKO kidney recipients developed minimal proteinuria (fig. 1 A-1, A-3, page S314 and results, paragraph 1, page S315). The study concludes that the high expression of hCD47 on porcine glomeruli may prevent proteinuria (results, paragraph 2, page S315).
Regarding claim 75, Nomura teaches that recipients of high glomerular hCD47 expressing kidneys developed beyond 120 days (results, paragraph 2, page S315) or ~ 4 months.
Regarding, claims 65 and 74, Tena teaches the measuring of hCD47 expression level by real-time PCR (page 2718, fig. 4D).
Regarding claim 67, 68, and 78 Wong teaches a glomerular specific promoter from the human nephrin gene. Wherein, the nephrin is expressed in podocytes which are highly specialized cells that make up the glomerular filtration barrier in kidney.
Regarding claims 69 and 79, Yamada teaches a miniature swine thymokidney ( fig. 1a, table 1, pages 33 and 34).
Regarding claims 70 and 80, Yamada teaches GalTKO miniature swine kidneys grafted into baboon recipients (page 33, paragraph 2, fig. 1a).
Regarding claim 71, Tena teaches GalTkO deficient, MHC-inbred Columbia/Sachs miniature swine, as evidenced by Watanabe et al. 2021 (animal donors, page 3) and Tena et al. 2017.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to modify the above mentioned teachings of Yamada that teaches GalTKO miniature swine kidneys, with Tena that teaches the generation of human CD47 (hCD47) bearing transgenic miniature swine, Wong that teaches a glomerular specific promoter from the human nephrin gene, El‐Rashid that teaches CD47 mediated AKI through inhibition of renal tubular autophagy to result in low expression of hCD47 in tubules of the kidney and Nomura that teaches the glomerular expression of hCD47 at levels sufficient to prevent or reduce the severity of proteinuria in a kidney transplant recipient. One of ordinary skill in the art would have been motivated to combine the teachings of Yamada, Tena, Wong, El-Rashid and Nomura to produce a GalTKO miniature swine kidney that expresses hCD47 in glomeruli at a level higher than its’ expression in kidney tubules, to prevent, glomerular phagocytosis by macrophages, AKI and development of proteinuria in kidney recipients. There would be reasonable expectation of success to combine the teachings of Yamada, Tena, Wong, and Nomura because, Yamada teaches the survival of their kidney in baboons for over 80 days, Tena teaches the evasion of phagocytosis by macrophages by the expression of hCD47, and Wong teaches a glomerular specific promotor that can be used to elevate the expression of hCD47 in glomeruli of the said kidneys at a level higher than its’ expression in the kidney tubules to prevent RTEC death associated AKI as taught by El-Rashid, and Nomura teaches the survival of the high glomerular hCD47 expressing kidney recipient baboons for over 120 days with minimal proteinuria and significantly low phagocytosis by macrophages.
Hence, the claimed invention as a whole was prima facie obvious.
Conclusion
No claim is allowed.
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/HASHANTHI KOMITIGE ABEYRATNE-PERERA/Examiner, Art Unit 1632
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632