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 ACTION
The instant application is in response to the papers filed on March 7, 2024. Pursuant to the amendment filed on March 7, 2024, claims 1, 3, 6-13 and 15-24 are currently pending. Claims 6-13 and 15-24 have been amended, and claims 2 and 14 have been cancelled in Applicant' s amendment filed on March 7, 2024.
Therefore, claims 1, 3, 6-13 and 15-24 are currently under examination to which the following grounds of rejection are applicable.
Priority
The instant application claims foreign priority 35 U.S.C. 119(a)-(d) to United Kingdom Patent 2102235.5 filed on February 17, 2021 and PCT Application No. PCT/EP2022/053910 filed on February 17, 2022. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Thus, the earliest possible priority for the instant application is February 17, 2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on August 16, 2023 was filed. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claims 1, 3, and 11 are objected to because of the following informalities:
Claims 1 and 3 employ a semicolon after the preamble of the claims when a comma before “comprising” is proper, due to semicolons being used to separate two related sentences.
Claim 11 recites, “is visible in on imaging,”; however, it appears the Applicant intended to include only one of these prepositions as the combination of “in” and “on” is incoherent. Appropriate correction is required.
Claim Rejections - 35 USC § 102
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 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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 3, and 6 are rejected under 35 U.S.C. 102(a)(1)(2) as being anticipated by Reid et al. (US 9,533,013 B2).
Regarding claim 1, Reid teaches the method for the administration of cells to a liver comprising; administering a suspension of liver cells to the biliary tree of the liver in the direction of decreasing biliary duct diameter, such that the liver cells engraft into the liver (“A method of repairing diseased or dysfunctional pancreas or liver is provided. The method involves preparation of a suspension of stem cells and/or progenitor cells such as biliary tree stem cells, hepatic stem cells, pancreatic stem cells or their descendants, committed progenitor cells, from healthy tissue of the patient or of the biliary tree of a non-autologous donor and engrafting the cells into the wall of bile ducts near to the organ to be treated.” (abstract); Figure 9 depicts route of delivery, “endoscope would be moved into the common duct and possibly into the common hepatic duct and there grafted into or onto the wall of the duct.” (col 8; col 5, ln 46-67)). The claim’s recitation of “liver cells” is being understood as encompassing liver stem/progenitor cells or their descendants taught by Reid. Moreover, in reference to the limitation of “administering a suspension of liver cells to the biliary tree of the liver in the direction of decreasing biliary duct diameter, ” Reid teaches this limitation as the introduction is initiated from the common duct which is the widest diameter of the biliary duct, and further along the diameter becomes narrower as depicted in Figures 1-3, and 9.
Regarding claim 3, the rejection to claim 1 is applied herein, and moreover Reid teaches a method of treatment of an individual with a diseased or damaged liver (“The cells are specifically introduced to the hepato-pancreatic common duct of the subject for treatment of pancreatic conditions or to the bile duct wall near to the liver for treatment of liver conditions and allowed to migrate to the pancreas or to the liver and expand and then rebuild part or the entirety of the diseased or dysfunctional organ.” (abstract)).
Regarding claim 6, dependent on claim 1, Reid teaches wherein the liver cells in the suspension are in the form of aggregates (col 11, ln 17-19).
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 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 1, 3, 6, 9, 13, 15-19, 24 are rejected under 35 U.S.C. 103 as being unpatentable over Vallier et al. (WO 2018/234323 A1; of record IDS filed on August 16, 2023) in view of Chen et al. (Technology 7.01n02 (2019): 46-55).
The applied reference (“Vallier”) has a common inventor with the instant application, whose earliest filing date is February 17, 2021. Based upon the earlier effectively filed date of the reference, December 27, 2018, it constitutes prior art under 35 U.S.C. 102(a)(1), which is well beyond the provisions of 102(a)(2). Therefore the prior art is excluded from the exceptions under 35 U.S.C. 103, and CANNOT be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Vallier is directed to methods for generating extrahepatic cholangiocyte organoids (ECOs) and their use in the treatment of a biliary disorder or a liver disease, comprising cholangiopathy (abstract, p 23, ln 14-31). Vallier teaches in Example 1, the ECOs were administered to a mouse model of extrahepatic biliary injury (EHBI) to mice with extrahepatic biliary injury, and resulted in biliary reconstruction (Sec. 2.3 (p 43)). The ECOs were in combination with PGA scaffolds wherein their function and cell markers were maintained (Sec. 2.3 (p 42)). The second example employed densified collagen tubular scaffolds with ECOs (Fig. 22, 24), wherein “A mid-portion of the native CBD [“common bile duct”] was removed and an ECO-populated collagen tube was anastomosed end-to-end to the proximal and distal duct remnants (Figure 24)… Biliary reconstruction was achieved in all animals transplanted with ECO-populated tubes, which were followed up for up to a month post transplantation.” (Sec. 2.4 (p 44)).
Lastly, Vallier teaches another example, “In addition, we generated ductopenia in NOD-SCID mice by administration of 4, 4'- methylenedianiline (MDA). The presence of duct damage following MDA administration was confirmed by H&E staining. Human ECOs engineered to express RFP were then injected into the mice and engraftment and the formation of neo-ducts by the RFP expressing ECOs assessed by immunofluorescence analysis. The formation of neo-ducts of different sizes in the mice and the retention of biliary marker expression (e.g. KRT19) was observed. These experiments demonstrate that expanded populations of cholangiocytes as described herein may be useful in cell based therapy against diseases affecting the liver, such as intrahepatic cholangiopathies, in addition to extra-hepatic cholangiopathies.” (p 45, ln 8-16).
Vallier does not teach the liver cells, e.g. cholangiocytes, are injected into the biliary tree in the direction of decreasing diameter (retrograde direction), but rather the cells are rejoined to the bile duct or attached to the surface of the biliary tree (Fig 24 and 18, respectively). Vallier does describe in the last example described above wherein the cells are injected into the mice, but the route of delivery remains unclear.
Chen teaches “In this study, we performed heterogeneous recellularization by repopulating the decellularized rat liver scaffolds with cholangiocytes and primary hepatocytes. The whole biliary structure, including intrahepatic biliary tree, was engineered by retrograde infusion of cholangiocytes through the common bile duct.” (p 3, par 2; p 5, par 2). The observed outcomes was an even distribution of cholangiocytes in both intrahepatic (peripheral) and central regions, and additionally lined the bile duct without going into the parenchymal spaces (p 9, par 4). Furthermore, based on gene expression analyses, the cholangiocytes appeared to remain viable and continued to express genes of functional proteins in the recellularized liver matrices, which may indicate active biliary metabolism (p 10, par 2; Fig. 4).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have administered a suspension of liver cells, e.g. cholangiocytes, to the biliary tree of the liver via retrograde delivery with the method taught by Chen because it would have been obvious to try this mode of delivery for cholangiocytes which line the inner bile duct, and secondly this delivery being successful with cholangiocytes, and lastly, as the person of ordinary skill would be choosing from a finite number of identified, predictable solutions for the delivery of liver cells to the biliary tree with a reasonable expectation of success. Therefore, there is an expectation that the cholangiocytes described by Vallier in treating liver diseases and disorders, would likely lead to similar outcomes when using the mode of delivery taught by Chen with cholangiocytes because the delivered cells are described as maintaining viability while being delivered to the appropriate regions of the biliary tree.
Regarding claim 3, the rejection to claim 1 is applied herein, wherein it describes that Vallier teaches a method of treatment of an individual with a diseased or damaged liver (abstract, p 23, ln 14-31).
Regarding claim 6, dependent on claim 1, Vallier teaches wherein the liver cells in the suspension are in the form of aggregates (“clusters”, p 23, ln 18-19).
Regarding claim 9, dependent on claim 1, Vallier teaches wherein the liver cells are cholangiocytes as seen in the rejection to claim 1.
Regarding claim 13 and 15, both dependent on claim 1, Chen teaches flushing the biliary tree of the liver with a wash solution comprising a buffer before administration of the suspension of liver cells (“Th e scaffold was flushed with PBS before cell seeding. In recellularizations with cholangiocytes only, no cells were introduced into parenchymal space, therefore, the liver scaffold was only perfused with PBS instead of culture media prior to the seeding. A total number of 1 or 1.8 million NRCs at passage 20 were injected into the common bile duct cannula in the DLM scaffold at a density of 4 million cells per mL using an insulin syringe.” (p 5, par 2, 3). Secondly, it would be obvious to flush the biliary duct that is diseased or damaged in order to improve therapeutic outcomes when using the expanded cholangiocytes provided by Vallier. For example, Vallier describes in Example 2 the removal of a mid-portion of the native CBD, and then addition of the expanded ECOs were able to reconstruct the biliary tract, and therefore it is expected that flushing of the biliary tract would improve therapeutic outcomes when followed by cellular transplants/injection(s).
Regarding claim 16, dependent on claim 3, the rejection to claim 8 is applied herein as it teaches the use of an anti-choleretic agent to reduce bile secretion in the culture medium, e.g. somatostatin, for which would be comprised in the cellular suspension provided to the subject. Moreover, it would be obvious to include somatostatin to confirm the functional properties of the provided cholangiocytes based on the hormonal response.
Regarding claim 17, dependent on claim 1, Chen teaches wherein the cell suspension is injected into the biliary tree through a catheter or cannula (“cannulated bile duct”, FIG 1C).
Regarding claim 18, dependent on claim 1, the rejection to claim 8 describes the use of a “non-adhesive reagent”, wherein the instant Specification provides an example as bovine serum albumin (p 9, par 3). Vallier teaches the culture medium as comprising bovine serum albumin (p 14, par 4). Moreover, it would be obvious to be motivated to coat the interior surface of the catheter or cannula with BSA to prevent cell adhesion in order to improve delivery of the cell suspension while minimizing occlusion of the biliary ducts.
Regarding claim 19, dependent on claim 1, Chen teaches wherein the method comprises retaining the suspension of liver cells within the biliary tree following said administration (p 9, par 4).
Regarding claim 24, dependent on claim 1, Vallier teaches cholangiocytes play important roles in bile secretion and electrolyte transport in vivo. (p 8, par 5).
Chen teaches “Biliary epithelial cells, also known as cholangiocytes, line the intrahepatic bile ducts and transport bile to the common bile duct, thus removing it from liver cells. Cholangiocytes also participate in bile modification such as alkalization through ion exchange, fluid and electrolytes secretion and reabsorption.” (p 3, par 2). Moreover, Chen analyzes gene expression of expanded cholangiocytes on recellularized grafts, wherein “Interestingly, AE-2 expression increased as well. AE-2 is a pH regulatory protein involved in epithelial acid-base mediation through secretion of HCO3. Diminished AE-2 activity was correlated with cell injury and biliary tree damage while increased intracellular pH levels lead to increased AE-2 activity. It is possible that the difference between the pH levels among the groups led to the slight increase in the AE-2 expression in recellularized grafts.
Altogether, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have been motivated to monitor changes in pH, electrolyte, and total bile volume after cell transplants into biliary tree based on the roles cholangiocytes have with altering these concentrations as described by Vallier and Chen.
Claims 7 and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Vallier et al. (WO 2018/234323 A1) in view of Chen et al. (Technology 7.01n02 (2019): 46-55) as applied to claims 1, 3, 6, 9, 13, 15-19, 24 above, and further in view of Katsuda et al. (US 2019/0302100 A1).
The disclosure of Vallier in view of Chen is applied as in the 103 rejections above, the content of which is incorporated above, in its entirety.
Regarding claim 7, dependent on claim 1, Vallier teaches the liver cells, e.g. cholangiocytes, are suspended in a culture medium comprising a buffer (p 14 – 15).
Vallier in view Chen does not teach the culture medium further comprising a Rho kinase inhibitor.
Katsuda teaches the medium in which human mature hepatocytes are cultured may further contain a ROCK inhibitor, for example “Y-27632 (CAS No. 146986-50-7), GSK 269962 (CAS No. 850664-21-0), Fasudil hydrochloride (CAS No. 105628-07-7), H-1152 (CAS No. 871543-07-6), with Y-27632 being preferred.” (par 0063). Katsuda teaches this by using “YAC” and/or YAC-F” medium which comprises Y-27632.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used a ROCK inhibitor in the culture medium for liver cells as described by Katsuda with the cholangiocytes as taught by Vallier because Katsuda was successful in expanding liver cells when using YAC medium, and therefore there is an expectation that the combination of a ROCK inhibitor in the culture medium of Vallier would lead to similar outcomes within a reasonable expectation of success.
Regarding claim 8, dependent on claim 7, Vallier teaches wherein the culture medium further comprises an anti-choleretic agent as seen in and/or a non-adhesive reagent as seen in the testing with somatostatin to determine the cells functional properties on water secretion (p 18, par 1). In reference to the “non-adhesive reagent”, the instant Specification provides an example as bovine serum albumin (p 9, par 3). Vallier teaches the culture medium as comprising bovine serum albumin (p 14, par 4).
Claims 10-12, 19-21, and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Vallier et al. (WO 2018/234323 A1) in view of Chen et al. (Technology 7.01n02 (2019): 46-55) as applied to claims 1, 3, 6, 9, 13, 15-19, 24 above, and further in view of Selaru et al. (US 2020/0345867 A1).
The disclosure of Vallier in view of Chen is applied as in the 103 rejections above, the content of which is incorporated above, in its entirety.
Regarding claim 10, dependent on claim 1. Vallier does not teach a method of injection into the biliary tree as described in the claim 1 rejection above, but does teach performing Magnetic Resonance Cholangio-Pancreatography (MRCP) to observe the biliary tree structure (Sec. 1.32)
Chen teaches injection of cholangiocytes into the biliary tree wherein the volume of the cholangiocyte suspension is an amount sufficient to only fill the file ducts at around 250 µL (p 9, par 4). Chen describes the amount of cells used was based on the average surface area of bile ducts in a normal rat liver and the doubling time of normal rat cholangiocytes. The seeding density was determined, and then further altered to prevent occlusion of the ducts while being fully lined with cholangiocytes (p 7, par 3).
Vallier and Chen do not teach wherein the method comprises measuring the volume of the biliary tree of the individual up to a desired site of engraftment and suspending the liver cells in a volume corresponding to the volume measured for the individual.
Selaru teaches injection of the bile duct for gene delivery liver cells in the biliary tree in which injection volumes and speed are determined based on swelling. Selaru performs an ERCP [Endoscopic Retrograde Cholangiopancreatography] wherein the common bile duct (CBD) and intrahepatic ducts are cannulated , the duodenoscope was placed in the short position enface to the biliary orifice. “contrast injection demonstrated that the diameters of CBD was 6-8 mm, CHD 3-5 mm and the main intrahepatic ducts 2 mm, respectively. Despite injecting volumes as high as 20 mL at rates of 4 mUs, no contrast medium escaped around the balloon into the CBD during hydrodynamic injection. This indicated that an adequate seal was created to facilitate the generation of hydrostatic pressure. Injecting volumes greater or equal to 20 mL, regardless of rate, demonstrated acinarization of the liver parenchyma indicating that contrast had exited the biliary tree. Injecting 40 mL at 2 mIJs resulted in rupture of the proximal CHD during the process of injection (FIG. 7).” (par 0179).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have been motivated to measure the volume of the biliary tree prior to injection with liver cells to determine the optimal volume for the cell suspension to target the maximal surface area for cellular regeneration of the biliary duct while preventing occlusion and extending outside of target sites as Chen describes. Moreover, it would be obvious to measure volume of the biliary tract as Selaru has done to prevent exiting of the cell suspension from the biliary tract, and subsequently improve therapeutic effectiveness based on a higher quantity of provided cells delivered.
Regarding claim 11, dependent on claim 10, Vallier teaches a method of using magnetic resonance cholangiopancreatography (MRCP) to observe structure of the biliary tree; as well as Fluorescein Isothiocyanate (FITC) cholangiogram both of which involve a contrast agent fluid (Sec. 1.31-1.32)
Regarding claim 12, dependent on claim 10, the rejection to claim 11 is applied herein as Vallier teaches using magnetic resonance imaging. Additionally, Selaru teaches both MRCP and ERCP (par 0032).
Regarding claim 20 and 21, both dependent on claim 19, Chen teaches the retention of cholangiocytes in the biliary tree after injection into the bile duct, but does not teach intentional occlusion, particularly by occluding the lumen of a bile duct of said tree to reduce or prevent egress of the suspension.
Selaru teaches “In some embodiments one or more vessels or ducts are occluded to reduce or prevent flow of the solution in one or more directions, for example, back flow.” (par 0101), moreover using an occlusion balloon in the biliary tree (par 0174, 0183).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used occlusion to limit the movement of the cholangiocyte suspension of Vallier in view of Chen to only the biliary tree based on using known occlusion methods of the biliary tree as described by Selaru in order to improve outcomes of cellular regeneration of these select tissues.
Regarding claim 23, dependent on claim 20, Vallier teaches the ECOs are seeded on scaffolds for 30-60 minutes to allow attachment (p 35, Sec. 1.18). Vallier does not teach wherein the biliary tree is occluded for 30 minutes or longer.
Chen teaches cholangiocytes were delivered over the course of 30 minutes, “Briefly, cholangiocyte populated and blank scaffolds were placed into two parallel perfusion setups and perfused for 30 minutes” (p 5, par 3).
Chen does not teach wherein the biliary tree is occluded for 30 minutes or longer.
Selaru teaches that “In certain aspects, the balloon can be kept inflated for just the duration of injection or for an extended period of time after the hydrodynamic injection/power injection is completed.” (par 0123).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have occluded for 30 minutes or longer based on Chen teaching the perfusion step being around 30 minutes to effectively target the biliary tree, and therefore it would obvious to occlude for this period time with the method of Selaru which teaches occlusion can occur for the amount of time it takes the injection to occur.
Claims 19, 20, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Vallier et al. (WO 2018/234323 A1) in view of Chen et al. (Technology 7.01n02 (2019): 46-55) and Selaru et al. (US 2020/0345867 A1) as applied to claims 1, 3, 6, 9, 13, 15-19, 24 above, and further in view of Blaskovich et al. (US 10,328,095 B2).
The disclosure of Vallier in view of Chen is applied as in the 103 rejections above, the content of which is incorporated above, in its entirety. Furthermore, regarding claim 20, the disclosure of Vallier in view of Chen and Selaru is applied as in the 103 rejections above, the content of which is incorporated above, in its entirety
Regarding claim 22, dependent on claim 20, Valier in view of Chen and Selaru teach the occlusion of biliary tree to reduce or prevent egress of the suspension as seen by Selaru teaching occlusion with balloons within the bile duct as described above in the claims 20 and 21 rejections.
Valier in view of Chen and Selaru do not teach wherein the biliary tree is occluded by biodegradable beads.
Blaskovich teaches occlusion by biodegradable beads, particularly oxidized cellulose microspheres that are effective in blocking the bile ducts (col 34, ln 10-38). The reference further states, “Oxidized cellulose embolization microspheres and the slurry offer distinct advantages, and significantly greater control than other embolization technologies due to adjustable degradation, dissolution, and/or swellability rates since oxidized cellulose offers a wide spectrum in terms of the kinetics of degradation as described above.” (col 38).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used employed the biodegradable spheres/beads described by Blaskovich occlude the biliary tree as it provides advantages not offered by a stent or balloon, which is primarily biodegradability, and therefore reduction in steps pertaining to removal of the occlusion device. Therefore, the usage of Blaskovich’s beads would lead to an improved method of occlusion by reduction relevant occlusion steps, and secondly, there is a reasonable expectation that the beads would function in occlusion based on Blaskovich teachings of the microspheres functioning in bile ducts.
Conclusion
Claims 1,3,6-13 and 15-24 are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MICHAEL A RIGA whose telephone number is (571)270-0984. The examiner can normally be reached Monday-Friday (8AM-6PM).
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/MICHAEL ANGELO RIGA/Examiner, Art Unit 1634
/TERESA E KNIGHT/Primary Examiner, Art Unit 1634