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 .
DETAILED OFFICE ACTION
This Office Action is in response to the papers filed on 22 October 2025.
CLAIMS UNDER EXAMINATION
Claims 11-13, 15-25 and 29 are pending and have been examined on their merits.
PRIORITY
Provisional Application 62/719,272, filed on 17 August 2018, is acknowledged. The Provisional Application does not provide support for a solid organ (claim 17) or the organs recited in claims 18-21. Support for these limitations is found in PCT/CA2019/051121 filed on 16 August 2019.
WITHDRAWN REJECTIONS:
The rejection of claims 11-13, 15-25 and 29 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, has been withdrawn due to claim amendment.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 11-13, 15-18 and 23-25 are rejected under 35 U.S.C. 103 as being unpatentable over Haruko et al. (Development of H-specificity in A Substance by A-Decomposing Enzyme from Clostridium tertium A. proc. Japan Acad., 44 1968) in view of Kobayashi et al. (Removal of blood group A/B antigen in organs by ex vivo and in vivo administration of endo-beta-galactosidase (ABase) for ABO-incompatible transplantation. Transpl Immunol. 2009 Jan;20(3):132-8. Epub 2008 Oct 7) and Earl et al. (The Broad Institute Genome Sequencing Platform 2011)
as evidenced by the National Cancer Institute (cited in IDS; definition of “red blood cell”), UniProt (cited in IDS N-acetylgalactosamine-6-phosphate deacetylase), NCBI (cited in IDS: Flavonifractor plautii Taxonomy) and GenCor (UNIPROT A0A096D861_FLAPL and UNIPROT A0A096B2Z8_FLAPL; see Office Action appendix).
Haruko et al. investigate A-decomposing enzymes from Clostridium tertium (see page 264, second paragraph). The art teaches enzymes that have the activity to destroy the A activity and to enhance the H activity in A substance (page 264, second paragraph). The art applies enzyme fractions to either “A substance or A red cells” (page 264, last paragraph). It is well known in the art that “red cells” are also called erythrocytes (definition by National Cancer Institute). Haruko teaches the enzyme in Fraction 4 destroys A activity, but H activity was not enhanced (page 264, last paragraph). Fraction 4 enzyme acts as deacetylase on N-acetylgalactosaminyl residue, a determinant of the A -specificity (see page 265, second paragraph). The enzymes in Fraction 31-34 enhance H activity and destroy A activity (same cited section).
Haruko teaches “when A substance or A red cells were first incubated with Fr. 4 deacetylase, and then with Fraction 31-34 enzyme, galactosamine was liberated with enhancement of the H activity. This indicates that the Fr. 31-34 enzyme preparation principally contains galactosaminidase and deacetylase” (first paragraph of page 266).
The art teaches “When the deacetylase contained in the A-decomposing enzyme is solely applied to A substance of A red cells, the A activity is destroyed without the H activity being enhanced. When, however, the galactosaminidase is acted together with the deacetylase, the H activity in A-substance is enhanced because if there is fucose in it… which has the capacity to exert H-specific action, H-specificity is developed by liberation of N-acetyl group and galactosamine which has inhibited it” (see page 267, second paragraph). Therefore the art teaches the use of both enzymes.
Haruko treats erythrocytes with enzymes from Clostridium tertium to cleave A-substance (A-antigen). Haruko teaches a galacosaminidase. Haruko also teaches a “deacetylase” which deacetylates a N-acetylgalactosaminyl residue. As evidenced by UniProt, N-acetylgalactosamine-6-phosphate deacetylase catalyzes the deacetylation of N-acetyl-D-galactosamine 6-phosphate to D-galactosamine 6-phosphate”. Examiner notes “GalNac” is N-Acetylgalactosamine. Therefore Haruko teaches a GalNacdeacetylase.
Claim 11 recites at least one of the galactosaminidase or GalNac deacetylase are derived from Flavonifractor plautii. This is a product by process limitation.
The deficiencies of Haruko are:
The art does not teach perfusing or incubating an organ with the enzymes.
The art does not teach at least one of the enzymes is derived from Flavonifractor plautii.
Kobayashi teaches ABO incompatibility in organ transplantation is still a high risk factor for antibody-mediated rejection, despite the progress in effective treatments (Abstract). The art teaches several bacterial exoglycosidases which can effectively cleave blood type A/B Ag, have been successfully identified for the production of universal red blood cells (RBC) (see page 133, left column, second paragraph).
Kobayashi produces endo-ß-galactosidase (ABase), which releases A/B antigen (page 133, left column, section 3.1 of Materials and Methods). Human A/B red blood cells (RBC) were digested with Abase (Abstract). Purified recombinant ABase was intravenously administered to a baboon (Abstract; section 3.5 of Materials and Methods). The art also teaches excised baboon kidneys were perfused with purified recombinant ABase and preserved at 4°C (Abstract; section 3.6 of Materials and Methods). Kobayashi teaches recombinant ABase removed A/B Ag from human RBC; (ii) in vivo and ex vivo administration of ABase demonstrated a marked reduction of A/B Ag in the kidney and liver; (iii) a possible strategy using ABase would include enzymatic digestion of A/B Ag during cold storage after organ retrieval and/or repeated in vivo infusion into the recipient until accommodation developed (see last paragraph on page 137, right column).
As evidenced by NCBI, “Flavonifractor plautii” is previously known as “Clostridium orbiscindens”. As evidenced by GenCor , Earl et al. (2011) disclose a galactosaminidase and a GalNAcDeacetylase can be derived from Flavonifractor plautii (Clostridium orbiscindens).
It would have been obvious to try perfusing an organ with the enzymes taught by Haruko. One would have been motivated to do so since Haruko teaches a method of using an enzyme to remove blood antigens on cells and Kobayashi teaches enzymes can be used to remove blood antigens on cells and tissues. In the instant case, one would do so to remove A antigen on an organ. Kobayashi teaches ABO incompatibility in organ transplantation is still a high risk factor for antibody-mediated rejection. The skilled artisan would perfuse an organ since Kobayashi teaches organs can be perfused with enzymes. One would have had a reasonable expectation of success since Kobayashi teaches organs can be treated with enzyme to remove blood antigens. One would have expected similar results since both references are directed to methods of removing blood antigens.
It would have been obvious to try using galactosaminidase from Flavonifractor plautii in the assay taught by Haruko. One would have been motivated to do so since Haruko uses a galactosaminidase obtained from Clostridium tertium and Earl teaches galactosaminidase can also be obtained from the Clostridium Flavonifractor plautii. Both enzymes catalyze the same reaction. Therefore they are interpreted to have similar properties. KSR B teaches it is rational to substitute one known, equivalent element for another to obtain predictable results. One would have had a reasonable expectation of success since the enzymes catalyze the same reaction. The following is noted from MPEP 2113:
“[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) (citations omitted). MPEP 2113 further indicates that “The Patent Office bears a lesser burden of proof in making out a case of prima facie obviousness for product-by-process claims because of their peculiar nature” than when a product is claimed in the conventional fashion. In re Fessmann, 489 F.2d 742, 744, 180 USPQ 324, 326 (CCPA 1974). Once the examiner provides a rationale tending to show that the claimed product appears to be the same or similar to that of the prior art, although produced by a different process, the burden shifts to applicant to come forward with evidence establishing an unobvious difference between the claimed product and the prior art product. In re Marosi, 710 F.2d 798, 802, 218 USPQ 289, 292 (Fed. Cir. 1983).
Therefore claim 11 is rendered obvious.
As evidenced by GenCor, Earl et al. disclose UNIPROT A0A096D861_FLAPL.
As evidenced by GenCor (Result 1), the sequence reads on Seq ID 2.
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942
752
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As evidenced by GenCor, Earl et al. disclose UNIPROT A0A096B2Z8_FLAPL.
As evidenced by GenCor (Result 1), the sequence reads on SEQ ID 9
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726
428
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Therefore claims 12-13 are included in this rejection.
Haruko teaches enzymes are eluted in a phosphate buffer (see page 264, third paragraph of Materials and Methods). The art does not explicitly teach a buffered extracellular solution. Kobayashi perfuses a kidney (supra). In the section titled “Ex vivo administration of ABase”, Kobayashi teaches perfusion with “UW solution” (see page 134, left column, section 3.6). The specification identifies “University of Wisconsin solution (UW)” as a buffered extracellular solution (see [00010] of PG Pub).
It would have been obvious to use the enzymes taught by Haruko in a kidney perfusion solution. One would have been motivated to do so since Haruko discloses enzymes that remove blood antigens and Kobayashi formulates enzymes that remove blood antigens in a buffered extracellular solution. One would have had a reasonable expectation of success since Kobayashi teaches enzymes can successfully be added to a kidney perfusion solution. One would have expected similar results since both references are directed to methods of removing blood antigens. Therefore claim 15 is included in this rejection. Because the solution taught by Kobayashi is used to perfuse a kidney, it is broadly interpreted to read on a kidney perfusion solution. Therefore claim 16 is included in this rejection.
Kobayashi treats a kidney and a liver (solid organs). Therefore claims 17-18 are included in this rejection.
Haruko teaches a galactosaminidase and a GalNacDeacetylase. Therefore they would be expected to have the properties recited in claims 23 and 25.
Haruko teaches the deacetylase acts at an pH optimum of 7.2 (page 265, second column). The galactosaminidase acts at a pH optimum of 6.8 (page 266, first paragraph). Therefore claim 24 is included in this rejection.
Therefore Applicant’s Invention is rendered obvious as claimed.
Claims 22 and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Haruko in view of Kobayashi and Earl as evidenced by GenCor as applied to claim 23 above, and further in view of Goldstein et al. (Enzymatic Conversion of Certain Sub-Type A and AB erythrocytes. Patent 4609627 1986).
Claim 11 is rendered obvious on the grounds set forth above. The teachings of the prior art are reiterated.
Haruko is silent regarding washing (claim 22)
Haruko teaches not teach the use of a crowding agent (claim 29).
Goldstein et al. teach a method of treating erythrocytes with a galactosaminidase to remove A-antigen (Abstract). Goldstein teaches the use of either free enzymatic form or disposing the enzyme on a support, such as dextran (hence, a crowding agent) (column 4, lines 51-55). The art teaches the enzyme-soluble support conjugate e.g. enzyme dextran conjugate has the same specificity and ability for removal of the A determinant from the surface of the red cells as the free enzyme preparation and can be reused and stored without loss of activity. The use of such a conjugate is desired since they can be used repeatedly and their use is not characterized by side reactions due to impurities in starting enzyme material as is the case when free enzyme is employed. See column 6, lines 41-65.
Goldstein teaches erythrocytes are washed following enzyme treatment to remove enzyme and adjust the pH to between 7.2-7.4 to re-equilibrate the erythrocytes (see column 5, lines 55-57).
It would have been obvious to combine the teachings of the prior art by washing an organ. One would have been motivated to do so since Haruko treats a method of removing blood antigens from cells using enzymes and Goldstein teaches washing cells after enzymatic removal of blood antigens. The skilled artisan would wash an organ, which is composed of cells, since Goldstein teaches washing removes enzyme following treatment and re-equilibrates the treated cells. One would have had a reasonable expectation of success since Goldstein teaches enzyme can be removed by washing after treatment. One would have expected similar results since each reference is directed to removing blood antigens. Therefore claim 22 is included in this rejection.
It would have been obvious to use a crowding agent in the method taught by Haruko. One would have been motivated to do so since Haruko treats a method of converting A-erythrocytes using enzymes and Goldstein teaches using a crowding agent in a method of converting A-erythrocytes using enzymes. One would use a crowding agent as an enzyme support, as taught by Goldstein, since it allows the enzymes to be used repeatedly and inhibits side reactions. One would have had a reasonable expectation of success since Goldstein teaches crowing agents can be used when converting erythrocytes. One would have expected similar results since both references using enzymes to convert erythrocytes. Therefore claim 29 is rejected.
Therefore Applicant’s Invention is rendered obvious as claimed.
Claims 19-21 are rejected under 35 U.S.C. 103 as being unpatentable over Haruko in view of Kobayashi and Earl as evidenced by GenCor as applied to claim 17-18 above, and further in view of Subramanian et al. (ABO-incompatible organ transplantation. International Journal of Immunogenetics. Volume 39, Issue 4 August 2012 Pages 282-290).
Claims 17-18 are rejected on the grounds set forth above. The teachings of the prior art are reiterated. Haruko removes blood antigen using enzymes. Kobayashi treats a kidney and liver (solid organs) with enzymes to remove blood antigens. The art does not treat a lung.
Subramanian et al. teach ABO blood group incompatibility remains an important barrier for all solid organ transplantation (page 285, right column, last paragraph). Subramanian identifies kidney, liver, lung and heart as solid organs subject to ABO incompatibility (page 283, left column, first paragraph). As evidenced by Subramanian, blood group antigens are expressed on red blood cells and other tissue cell membranes (see page 283, left column, second paragraph).
It would have been obvious to try treating a lung. One would have been motivated to do so since Kobayashi treats solid organs that have blood antigens and Subramanian teaches the lung is a solid organ with blood antigens. One would have had a reasonable expectation of success since Kobayashi teaches enzymes can be used to remove blood antigens and Subramanian identifies lung as a solid organ with blood antigens. One would have expected similar results since both references are directed to solid organs with blood antigens. Therefore claim 19 is included in this rejection.
It would have been obvious to use the enzymes taught by Haruki to perfuse an organ for the reasons set forth in the rejection of claim 11.Claim 20 recites an ex vivo buffered extracellular lung solution. The claim does not recite the components of said solution. In the section titled “Ex vivo administration of ABase”, Kobayashi teaches perfusion of an organ with “UW solution” (see page 134, left column, section 3.6). The specification identifies “University of Wisconsin solution (UW)” as a buffered extracellular solution (see [00010] of PG Pub). Therefore the solution taught by Kobayashi, used for ex vivo administration, is interpreted to be an ex vivo buffered extracellular lung solution. Because the art teaches perfusion, it is interpreted to circulate through an organ.
Therefore claim 20 is rendered obvious.
Kobayashi teaches biopsies are taken before a 1 and 4 hours after perfusion (see section 3.6). Kobayashi teaches antigen is removed (supra). Therefore claim 21 is rendered obvious.
Therefore Applicant’s Invention is rendered obvious as claimed.
APPLICANT’S ARGUMENTS
Argument 1: The arguments state the UniProt deposits by Earl are predicted polypeptide sequences. The Applicant argues the Office Action does not establish they were publicly known to have similar, or have the same catalytic activity as the enzymes in Haruko. The applicant argues enzymes from F. plautii were found to be unexpectedly superior to enzymes from Clostridium tertium (the enzymes taught by Haruko).
Response to Argument 1:
Claim 11 does not recite any polypeptide sequences. The claim only requires one enzyme be derived from F. plautii. The claim does not recite which enzyme is derived from F. plautii. While the Applicant argues unexpected results, the instant specification states “neither of the enzymes used individually released any sugar products” when enzymes from F. plautii are incubated with red blood cells (RBCs) ([00182]). Therefore the fluid in claim 11, which requires only one F. plautii enzyme, would not release any sugar product from cells. The arguments are not commensurate in scope with the results argued by the Applicant.
The specification does not define the term “derived”. This is a product by process limitation that does not distinguish the enzymes taught by Haruko from those recited in claim 11. The rejection of claim 11 does not rely upon the sequences taught by Earl et al. Earl (2011) is relied upon because it teaches a GalNacdeacetylase and a galactosaminidase can be derived from F. plautii cells. Haruko uses a galactosaminidase obtained from Clostridium tertium and Earl teaches galactosaminidase can also be obtained from the Clostridium Flavonifractor plautii. Both enzymes catalyze the same reaction. Therefore they are interpreted to have similar properties. KSR B teaches it is rational to substitute one known, equivalent element for another to obtain predictable results. Absent evidence to the contrary, one would have had a reasonable expectation of success since the enzymes catalyze the same reaction.
Argument 2: The arguments state the claimed invention is supported by unexpected results as shown in Examples 10-14. The arguments state the examples describe how the present inventors, starting from their newly discovered
Flavonifractor plautii ("Fp") enzymes used similarity to identify in Clostridium
tertium ("Cf") a natural fusion protein having both GalNAcDeacetylase and
Galactosaminidase activities. The Fp enzymes were found to be unexpectedly superior to the Ct enzymes.
The arguments state Table 5 compares 1) Fp enzymes together against the CT fusion protein. The arguments state the CT fusion protein “stands in for Haruko” shows no detectable activity. Unexpectedly the Fp proteins together completely cleave the A-antigens in this assay.
The arguments state Example 12 shows the enzyme composition comprising F. plautii GalNAcDeacetylase protein of SEQ ID 5 and F. plautii Galactosaminidase of SEQ ID 10 is fully compatible with STEEN and Perfadex perfusion/preservation fluids enhanced the enzyme composition’s efficiency compared to PBS. The composition requires an increased enzyme concentration when PBS is used compared to STEEN and Perfadex.
Response to Argument 2: The unexpected results pointed to by the Applicant require “Fp enzymes together”. Claim 11 only requires one enzyme derived from F. plautii.
The instant specification states “neither of the enzymes used individually released any sugar products” when incubated with red blood cells (RBCs) ([00182]).
The Applicant uses a fusion protein to “stand in for Haruko”, but Haruko does not teach a fusion protein. Haruko discloses two enzymatic fractions.
The Applicant argues the claimed enzymes have enhanced enzymatic activity in STEEM and Perfadex. The experiments pointed to by the Applicant required SQ ID 5 and SEQ ID 10 in STEEN and Perfadex. None of the claims require STEEN or Perfadex. Therefore the unexpected results are not commensurate with the scope of the claims.
CONCLUSION
No Claims Are Allowed
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 extension fee 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NATALIE MOSS whose telephone number is (571) 270-7439. The examiner can normally be reached on Monday-Friday, 8am-5pm EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sharmila Landau can be reached on (571) 272-0614. The fax phone number for the organization where this application or proceeding is assigned is (571) 273-8300.
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/NATALIE M MOSS/ Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653