DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed 10/3/25 in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 10/3/25 has been entered.
Claims 40-46 have been amended.
Claim 56 has been added.
Claims 41-46 and 49-56 are pending.
Claim 49-52 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention. Claim 54 is withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected species.
Claims 40-46, 53, and 55-56 are being acted upon.
The previous grounds of rejection are withdrawn in view of Applicant’s claim amendments.
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 41, 43-46, and 55-56 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.
Claim 41 is indefinite in the recitation that the “plate passage” comprises subjecting the blood sample to a physical force by passing said blood sample through a “flow chamber of a device”. Is the flow chamber the plate passage? In other words, does the claim require a flow chamber that is a plate to meet the limitation of “plate” passage? Or do the claims require another step involving a plate in addition to passage through the flow chamber. The scope of the claims is unclear and indefinite.
Claim 43 recites the limitations “the design and dimensions”, “the flow rate”, “the temperature”, “the exposure”, “the density”, “the order in which the monocytes, platelets, platelet-derived factors and/or plasma components” throughout the claim. There is insufficient antecedent basis for these limitations in the claim.
Claim 55 is indefinite in the recitation of “non-natural” nucleobases. It is not clear whether the claim requires non-naturally occurring nucleobases, or whether the claim would encompass an RNA with a nucleobase other than A, U, C, and G. The instant specification discloses non-natural nucleobases (i.e. nucleobases other than A, U, C and G), but it is not clear if this is limiting definition or merely exemplary. For the purposes of examination, the claim is being interpreted to encompass any nucleobase other than A, U, C, and G. For example, the claims would encompass a naturally occurring nucleobase such as pseudouridine, since it is a nucleobase other than A, U, C, and G. Amendment to the claim to recite that the RNA contains a nucleobase other than A, U, C, and G would be remedial.
Claim 56 is indefinite in the recitation that the RNA “comprises chemically modified nucleic acids”. The instant specification discloses nucleic acids, such as RNA, may be chemically modified, i.e. a chemical derivative thereof. However, the present claims recite a RNA comprising “chemically modified nucleic acids”. It is not clear if the claims are meant to encompass an RNA further comprising a chemical modified nucleic acid, i.e. an RNA linked to a chemically modified DNA, for example? Or are the claims intending to be directed to a RNA that is chemically modified. For the purposes of examination, the claim is being interpreted as encompassing chemically modified RNA. Amendment to recite that the RNA is chemically modified would be remedial.
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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 40-46, 53, and 55-56 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. This is a new matter rejection.
The specification and the claims as originally filed do not provide support for the invention as now claimed, specifically:
A) A method comprising combining globally activated monocytes with RNA encoding an immunogenic antigen (Claim 40, and dependent claims).
B) A method comprising activating monocytes “through plate passage” (Claim 40 and dependent claims 42, 53, and 46).
Applicant indicates that support for the new limitations can be found at pages 23-24 of the specification. A review of the specification fails to reveal support for the new limitations.
Regarding A), at pages 23-24 the specification discloses producing globally activated monocytes, wherein there is no combination or co-incubation with disease effector cells or disease associated antigens before re-introduction of the monocytes, and that the monocytes are not contacted with disease associated antigens outside the body. The specification teaches that the globally activated monocytes are not contacted with disease associated antigens outside the body, but that the monocytes are introduced into a patient where they can take up tumor associated antigens. The present claims encompass combining an extracorporeal quantity of globally activated monocytes with RNA encoding an antigen to obtain globally activated monocytes displaying immunogenic antigens, i.e. contacting outside the body, which is specifically excluded in pages 23-24. Furthermore, pages 23-24 do not mention RNA encoding an antigen. On page 41, the specification discloses that in one embodiment, dendritic cells are loaded with immunogenic antigens, wherein the immunogenic antigens comprise RNA. Even if this is to be understood as RNA encoding an immunogenic antigen, the disclosure relates to combining dendritic cells with RNA, while the present claims are directed to combining “globally activated monocytes” with RNA. The specification does not contemplate combining extracorporeal globally activated monocytes with RNA encoding an immunogenic antigen, as recited in the present claims
Regarding B), the specification discloses producing globally activated monocytes by passing monocytes through a flow chamber of a device as recited in present claim 41. However, claim 40 broadly encompasses activation via “plate passage”. In the background section of the instant specification on page 3, the specification discusses a prior art process of extracorporeal photopheresis (ECP) by which leukocytes are passed through a polystyrene plate under flow conditions which provide a physical force, commonly termed “plate passage”. However, the present claims recite no limitations requiring ECP plate passage, and it is not clear that the background teaches regarding prior art ECP plate passaging are even part of the claimed invention. It is noted that “plate passaging” is also used in the art to describe the process by which cells are passaged, or transferred, from one plate to another (See Yoshida, entire document, E6, in particular). Therefore, the broadest reasonable interpretation of claim 40 would encompass activating the monocytes by plating and passaging or transferring the monocytes to a new plate. However, the only method of activating monocytes disclosed by the instant specification is the process of claim 41, and therefore, claim 40 has a broader scope than what is disclosed or contemplated in the instant specification.
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.
Claim(s) 40-46 and 53 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO 2014/106629 (of record), in view of Ponsaerts, 2002.
WO 2014/106629 teaches a method for obtaining immune stimulatory dendritic cells comprising providing an extracorporeal quantity of human subjects blood comprising monocytes, activating said monocytes and inducing their differentiation into immunostimulatory APCs in the absence of apoptotic agents and without cytokines cocktails (see page 5, 7-8, and 11). WO 2014/106629 teaches that the monocytes are activated by subjecting said blood sample to a physical force by passing the blood through a flow chamber that allows for tunable adjustment of flow rate and the application of shear force (See page 9 and 35-36, in particular). WO 2014/106629 teaches that the process of producing the immunostimulatory APC includes a global monocyte activation step, and a subsequent differentiation to immunostimulatory antigen presenting cell step (See page 7, in particular). WO 2014/106629 teaches that the activation of the monocytes occurs from the physical forces during the initial purification of the monocytes that can be further improved during the passage through the device (See pages 7-8). WO 2014/106629 exemplifies the process by passing the monocytes through plates of the flow chamber device (i.e. “plate passage”) to activate the monocytes, wherein the monocytes are then collected and incubated for a day, whereby they exhibit a dendritic cell phenotype (see Fig. 9,pages 97-99, in particular). In other words, the reference teaches that the process of applying the monocytes to the flow chamber induces globally activated monocytes, and initiates a differentiation process that occurs during a second step in the overnight incubation to provide for immunostimulatory dendritic cells
WO 2014/106629 teaches that activation is induced via interaction with platelets and/or plasma components and in the absence of apoptotic agents (see page 37-38, in particular). WO 2014/106629 teaches that the activation is influenced by the flow rate. WO 2014/106629 teaches that the monocytes can be activated by passing monocytes together with plasma components and platelets through said flow chamber and applying a physical force (see pages 9 and 35-38). WO 2014/106629 teaches a rectangular flow chamber having a height and width of 5 to 500 uM, and that a height and width below about 50 of 100 um are preferred (see pages 57). WO 2014/106629 teaches a flow chamber providing for a final volume of 1ml to about 30 ml (see page 50, in particular). WO 2014/106629 teaches a flow rate producing a force of 0.01 to 20 dynes/cm2 (see page 46, in particular). WO 2014/106629 teaches that once immune-stimulatory autologous dendritic cells have formed, they may be processed for specific purposes, such as by loading them with immunogenic antigens.
The reference differs from the claimed invention in that it does not explicitly teach loading with antigen by combining the activated monocytes with an RNA encoding an immunogenic antigen.
Ponsaerts teaches that dendritic cells can be loaded with antigen by contacting dendritic cells with an mRNA encoding an antigen, or alternatively by combining with said mRNA at the monocyte stage, followed by differentiation of said monocytes into dendritic cells (see materials and methods and page 1674, in particular). Ponsaerts teach providing the mRNA by in vitro transcription (i.e. separately from the cells). Ponsaerts teaches that mRNA loading at the monocyte stage is advantageous, since it provides a reduction in time and consumables for preparation of antigen loaded dendritic cells (See abstract in particular).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made load the monocytes with mRNA, as taught by Ponsaerts, as the method of providing dendritic cells with antigen in the method of WO 2014/106629. The ordinary artisan would be motivated to do so with a reasonable expectation of success, since Ponsaerts teaches that mRNA loading at the monocyte stage is advantageous, since Ponsaerts teaches that doing so provides a reduction in time and consumables for preparation of antigen loaded dendritic cells. One could envision loading the monocytes either before or after the flow chamber step and doing so would also involve choosing among a finite number of predictable options which could be pursued with a reasonable expectation of success. A person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense (see KSR International Co. V. Telefex Inc 82 USPQ2d 1385).
Claim 55-56 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO 2014/106629 and Ponsaerts, as applied to claim 40 above, and further in view of Kariko, 2008 (of record).
The teachings of WO 2014/106629 and Ponsaerts are described above.
The references differ from the claimed invention in that they do not explicitly teach an RNA comprising non-natural nucleobases or a chemically modified RNA.
Kariko teaches that incorporation of pseudouridine into mRNA for modification of dendritic cells and that doing so yields a superior translation capacity and biological stability.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to use mRNA containing pseudouridine as taught by Kariko, as the mRNA in the method made obvious by WO 2014/106629 and Ponsaerts. The ordinary artisan would be motivated to do so, since Kariko teaches that it yields superior translation capacity and biological stability. The instant specification teaches that non-natural nucleobases are those other an A, U, C, and G, and therefore, the RNA containing pseudouridine would be within the scope of a non-natural nucleobase of the instant claims. Furthermore, as pseudouridine represents a chemically modified isomer, it would also be within the scope of a chemically modified nucleic acid.
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP §§ 706.02(l)(1) - 706.02(l)(3) for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 40-46, 53, and 55-56 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 51-64 of copending Application No. 17,510,981, in view of 11,179,417 (of record), Ponsaerts, 2002, and Kariko, 2008 (of record).
The ‘981 application claims a method of inducing differentiation of monocytes into immunostimulatory antigen presenting dendritic cells comprising subjecting an extracorporeal quantity of mammalian subjects blood which comprises monocytes to a physical force to activate the monocytes. The ‘981 application claims that the method is performed in the absence of photoactivatable agents and UVA or without molecular cytokine cocktails. The ‘981 application claims that the force is provided by passing the blood through a flow chamber (i.e. “plate passage”), and that the monocytes are also activated by interaction with activated platelets or plasma components, and that the flow chamber allows for tunable adjustment of flow rate. The ‘981 application claims that the dendritic cells present an antigen, such as microbial or cancer antigen. The other parameters of the claims such as the flow rates and size of the chamber are optimizable based on the teachings of the ‘117 patent which details parameters that are used to for obtaining activated antigen presenting cells and dendritic cells using the same flow chamber process as the instant claims.
As taught by the ‘117 patent, the process of producing immune stimulatory dendritic cells using a flow chamber and sheer force is a two-step process, wherein passage through the flow chamber/sheer force results in a global monocyte activation step and thereafter the activated monocytes further differentiate into dendritic cells (see column 14 and 17 in particular). The ‘117 patent exemplifies the process by passing the monocytes through plates of the device to activate the monocytes, wherein the monocytes are then collected and incubated for a day, to achieve a dendritic cell phenotype (see columns 51-52 and the drawings in particular). In other words, the reference teaches that the process claimed in the ‘981 application induces globally activated monocytes as an intermediate stage in the differentiation process, which occurs as a result of passage through the flow chamber, and that subsequently the cells acquire an immunostimulatory dendritic cell phenotype during further culture of the cells. It would be obvious to load the APC of the ‘981 application with an mRNA encoding an antigen, by providing it to the activated monocyte cells before differentiation to dendritic cells during the subsequent culture based on the teachings of Ponsaerts for the same reasons set forth above. Furthermore, it would be obvious to use chemically modified or non-natural nucleotides based on the teachings of Kariko for the same reasons set forth above.
Claims 40-46, 53, and 5-565 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of US patents 8524495, 9321991, 10874418, 109345526, 8313945, 7109031, or 6524855, in view of WO 2014/106629, Ponsaerts, 2002, and Kariko, 2008.
The patents all claim a method of producing dendritic cells or immunostimulatory APC comprising applying an extracorporeal quantity of blood comprising monocyte or buffy coat (i.e. comprising monocytes) through a plastic treatment device wherein the cells interact with platelets and plasma components and are subjected to sheer force, and wherein the cells are further incubated to provide for functional APC or dendritic cells. The teachings of WO 2014/106629 are described above, and the other parameters of the claims such as the flow rates and size of the chamber are optimizable based on the teachings of WO 2014/106629 which details parameters that are used to for obtaining activated antigen presenting cells and dendritic cells using the same flow process and device of the instant claims. It would be obvious to perform the method claimed in the patents in the absence of apoptotic agents and cytokines, since WO 2014/106629 teaches that doing so is optimal for obtaining immunostimulatory APC or dendritic cells.
As noted above, WO 2014/106629 teaches that the process of producing immune stimulatory dendritic cells using a flow chamber and sheer force is a two-step process, wherein passage through the flow chamber/sheer force results in a global monocyte activation step and thereafter the activated monocytes further differentiate into dendritic cells. WO 2014/106629 exemplifies the process by passing the monocytes through the plates of the device to activate the monocytes, wherein the monocytes are then collected and incubated for a day, to achieve a dendritic cell phenotype. In other words, the reference teaches that the process claimed in the patents induces globally activated monocytes as an intermediate stage in the differentiation process, which occurs as a result of passage through the flow chamber under sheer force, and that thereafter the cells acquire an immunostimulatory dendritic cell phenotype during subsequent culture of the cells. It would be obvious to load the dendritic cells of the patents with an mRNA encoding an antigen, by providing it to the activated monocyte cells before differentiation to dendritic cells during the subsequent culture based on the teachings of Ponsaerts for the same reasons set forth above. Furthermore, it would be obvious to use chemically modified or non-natural nucleotides based on the teachings of Kariko for the same reasons set forth above.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMY E JUEDES whose telephone number is (571)272-4471. The examiner can normally be reached on M-F from 7am to 3pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Dan Kolker, can be reached at telephone number 571-272-3181. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Amy E. Juedes
Patent Examiner
Technology Center 1600
/AMY E JUEDES/Primary Examiner, Art Unit 1644