DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
The preliminary amendment filed 5/26/2023 has been received and entered into the application file. The replacement drawings filed 6/23/2023 have been received and entered into the application file. Claims 233-253 are pending, all of which have been considered on the merits.
Priority
Acknowledgment is made of Applicants’ claim for benefit as a continuation of prior-filed US application 15/902817 (filed 2/22/2018, now US Patent 11566228), which claims benefit as a continuation of prior-filed US application 14/869561 (filed 9/29/2015, now US Patent 9938500), which claims benefit as a continuation of prior-filed US application 13/190988 (filed 7/26/2011, abandoned), which claims benefit as a continuation of prior-filed US application 11/787,262 (filed 4/4/14, US Patent 8017393), which claims benefit of US Provisional applications 60/792224 (filed 5/19/2006), 60/846163 (filed 9/20/2006), 60/852142 (filed 10/16/2006), 60/860676 (filed 11/22/2006), and 60/918832 (filed 3/19/2007).
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 233-253 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Applicant's specification is found enabling for generating CD34-/CD31- human hemangio-colony forming cells in vitro, by:
(a) culturing human embryonic stem cells (hESCs) in serum free Stemline media supplemented with VEGF and BMP-4 to induce differentiation of said hESCs into embryoid bodies (EBs);
(b) culturing the EBs from step (a) for between about 2-6 days in serum-free Stemline media supplemented with VEGF, BMP-4, TPO, Flt3, SCF, and optionally TBD-HOXB4;
(c) disaggregating the EBs into single cells; and then
(d) culturing the disaggregated cells in serum-free BL-CFU/hemangioblast expansion medium comprised of 1% methylcellulose in IMDM, supplemented with bovine serum albumin, mercaptoethanol, insulin, transferrin, GM-CSF, IL-3, IL-6, G-CSF, EPO, SCF, FLt3 ligand, VEGF, BMP-4 and tPTD-HoxB4, and optionally with FL and TPO to generate CD34-/CD31- human hemangio-colony forming cells.
Applicant's specification is not found to be enabling for methods for generating any type of ‘hemangio-colony forming cell’ other than CD34-/CD31- hemangio-colony forming cells. Applicants’ specification is not found to be enabling for generating any type of hemangio-colony forming cell by a method which generically involves:
(a) culturing hESCs in a serum-free media comprising one or more of VEGF and BMP-4 for promoting formation of EBs;
(b) culturing the cells of (a) in any serum-free media other than Stemline media supplemented with less than VEGF, BMP-4, TPO, Flt, and SCF, thereby forming EBs;
(c) disaggregating the EBs created in step (b); and then
(d) generating hemangio-colony forming cell by culturing the disaggregated cells in any media other than serum-free BL-CFR/hemangioblast expansion media containing 1% methylcellulose in IMDM, supplemented with bovine serum albumin, mercaptoethanol, insulin, transferring, GM-CSF, IL-3, IL-6, G-CSF, EPO, SCF, FLt3 ligand, VEGF, BMP-4 and tPTD-HoxB4.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to carry out the method of the invention commensurate in scope with the current claims.
Analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention without undue or unreasonable experimentation. See Mineral Separation v. Hyde, 242 U.S. 261, 270 (1916). The key word is 'undue,' not experimentation.' " (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all these factors are considered, a sufficient number are discussed below so as to create a prima facie case.
Applicants' claims are directed to a method of generating “human hemangio-colony forming cells.” Neither the specification nor the art, at the time the invention was made, provide a clear definition for this cell phenotype. At the time the invention was filed, there was no consensus in the art as to what specific characteristics/molecular markers defined/identified a human hemangio-colony forming cell (hemangioblast). Hemangioblasts, in general, are defined as cells capable of giving rise to both hematopoietic cells and endothelial cells; this is required by the claims. Yet, at the time the application was filed several groups had isolated human cells that had demonstrated the capacity to give rise to both hematopoietic cells and endothelial cells; however, each group used different culture conditions, and thus it was possible that the cells isolated by each group were not identical. Even two years after the filing of the instant work, no consensus had been reached in the scientific community as to what composite of molecular markers characterize human hemangioblasts (See Xiong et al, Developmental Dynamics, 2008, paragraph spanning pages 1220-1221). The specification defines "human hemangio-colony forming cells" (used synonymously with "hemangioblast") as cells "capable of differentiating to give rise to at least hematopoietic cell types or endothelial cell types" (emphasis added) (See PGPub, paragraph 0186). (The sentences following this definition, which read “Hemangio-colony forming cells are preferably bi-potential and capable of differentiating to give rise to at least hematopoietic cell types and endothelial cell types” is not limiting, due to use of the term “preferably”.) This definition is actually repugnant to the art, in that it permits for inclusion of cells which are only uni-potent, whereas hemangioblasts must be bi-potent. Thus, the term “human-hemangio-colony forming cells” on its own, does not describe any particular cell type. The claims do limit the human hemangio-colony forming cells as having the functional limitation ‘capable of differentiating into hematopoietic cells and endothelial cells’, but as stated above, this may encompass multiple different cell types. This lack of specificity is problematic, because the active steps of the method for creating this cell type are written in such broad language that they are only limited by the end point. Because the end point (human hemangio-colony forming cells) is not clearly defined, then the steps taken to get to the end point must be defined in order to enable one to successfully carry out the method as claimed.
The steps taken to get to the end point are not clearly defined, but rather are very broad/generic. Step (a) requires culturing a hESC in the presence of VEGF and/or BMP4, but provides no limits on other media components, duration of culture, nor functional limitation (i.e. what effect is achieved by the culture). Thus step (a) covers culturing any hESC in any media that contains even a single molecule of VEGF or BMP4 for any period of time, no effect is required by this step. The limitation “promoting the formation of EBs” is not the same as “forming EBs”. Step (b) requires further culturing the hESCs from step (a) (which may be unchanged from the original hESCs), in any media that comprises any amount of at least two of VEGF, BMP-4 and bFGF. The effect of this step must be to form EBs. Step (c) requires disaggregating the EBs into single cells. Step (d) requires culturing the single cells in a serum free media comprising at least two growth factors selected from the group consisting of: insulin, transferrin, GM-CSF, IL-3, IL-6, G-CSF, SCF, TPO, FL, VEGF and BMP-4, thereby generating human hemangio-colony forming cells. The claim covers 55 different combinations of ‘at least two growth factors’, one of which is VEGF and BMP-4, which is the same combinations permitted in steps (a) and (b). Thus the EBs may be disaggregated and continued to be cultured in the same media. This step must result in generation of human hemangio-colony forming cells.
At the time the invention was made there was a high level of unpredictability in the art surrounding generation of human hemangio-colony forming cells. Methods for generating hemangio-colony forming cells from mouse ESCs were known (See Choi et al, Development, 1998), but the same culture techniques were not successful with human cells. Many groups were working on identification of and isolation of a human hemangio-colony forming cell from the human EB model, but prior to Applicants, none had succeeded (See, Wang et al, Immunity, 2004; Zambidis et al, Blood, 2005). Therefore, the field to which the instant application is directed was nascent and unpredictable. Due to the lack of teachings in the art regarding conditions appropriate for generating hESC-derived hemangio-colony forming cells, and the recognized unpredictability in the area, the burden of enablement falls entirely on Applicants' disclosure to enable for the full breadth of the claims as written. Applicants are pioneering a new field (at the time of filing), and thus must give sufficient information to permit one having ordinary skill in the art to follow their teachings and successfully carry out the method for the full breadth of the claims.
Applicants’ specification, while lengthy, only exemplifies one base method for generating human hemangio-colony forming cells from hESCs. The details of the base method are pieced together from the information in Examples 1 and 2, and is described in detail at the beginning of this rejection (in the paragraph beginning with “Applicant specification is found enabling for...”). A variation on the base method involves the optional inclusion of TBD-HOXB4 in step (b) and FL and TPO in step (d). The breadth of the claims is much greater than this single base method demonstrated by the specification.
In light of the state of the art, discussed above, which recognizes a high level of unpredictability in the field of generating human hemangio-colony forming cells, it is not appropriate to extrapolate the much broader scope, as claimed, from the very narrow working example disclosed by Applicants. The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). One having ordinary skill in the art would be faced with the undue burden of figuring out what growth factors and what culture conditions for steps (a), (b) and (d) would satisfactorily yield ‘human hemangio-colony forming cells’. Furthermore, given the undefined end point (human hemangio-colony forming cells) it is impossible to simply optimize to achieve the desired endpoint.
Therefore, due to the sum of all the aforementioned factors, one of ordinary skill in the art, at the time the invention was made, would be faced with the impermissible burden of undue experimentation in order to determine which culture conditions other than those specifically described at the beginning of this rejection (if any) would successfully generate human hemangio-colony forming cells.
Double Patenting
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.
This provisional NSDP rejection was previously dropped because it was the last remaining rejection in the case, and the instant application had the earlier effective filing date of the two applications. However, with reinstatement of the rejection above, the claims are no longer considered in condition for allowance, and so the provisional NSDP is reinstated:
Claims 233-253 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-69 of U.S. Patent No. 8017393.
Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claims anticipates the instant claims.
Patented claim 1 recites a narrower embodiment that falls within the scope of instant claims 233, 238, 239, and 241.
Dependent patented claims teach each and every limitation of the instant dependent claims 234-237, 240 and 242-253.
Claims 233-253 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 9938500.
Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claims anticipates the instant claims.
Patented claim 1 recites a narrower embodiment that falls within the scope of instant claims 233, 236, 238, and 239.
Dependent patented claims teach each and every limitation of the instant dependent claims 234, 235, 237, 240-253.
Claims 233-253 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11566228.
Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claims anticipates the instant claims.
Patented claim 1 recites a narrower embodiment that falls within the scope of instant claims 233, and 251
Dependent patented claims teach every limitation of the instant dependent claims 234-250 and 252-253.
Claims 233-253 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 185-200 of copending Application No. 16/690888 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because the reference claims anticipate the instant claims.
Regarding instant claims 233 and 241: Co-pending claim 185 encompasses a method comprising:
culturing human pluripotent stem cells in a first serum-free media comprising VEGF and BMP4 to generate EBs (which reads on instant claim 233 steps (a) and (b);
disaggregating the EBs (which reads on instant claim 233, step (c)); and
(c) culturing the disaggregated EB cells in second serum free medium comprising TPO, FL and bFGF to generate human hemangio-colony forming cells (which reads on instant claim 233, step (d) and limitations of claim 241).
Co-pending claim 185 differs from instant claim 233 in that they refer to a human pluripotent stem cell, whereas the instant claims culture a human ESC. It is submitted that human embryo-derived cells are examples of human pluripotent stem cells. Furthermore, co-pending claim 186 defines the human pluripotent stem cell as human embryonic stem cell. Thus selection of hESCs as the pluripotent stem cell is at least prima facie obvious.
Regarding instant claims 234-236 and 242-245: Following the discussion of claim 233 above, determination of culture times for each step, and exact concentrations of each cytokine is considered to have been prima facie obvious as a matter of routine optimization.
Regarding instant claim 238: Inclusion of EPO in each of (a), (b) and (d) is rendered obvious by co-pending claims 189 and 191.
Regarding instant claim 239: Inclusion of HOXB4 in (d) is rendered obvious by co-pending claim 191.
Regarding instant claim 240: Use of methylcellulose is rendered obvious by copending claim 196.
Regarding instant claims 246-249: The co-pending claims do not specifically disclose separating the human hemangio-blasts colony forming cells produced; but such isolation steps and means for isolation are considered prima facie obvious to one having ordinary skill in the art. The technique of isolating the cell from a culture is part of the general knowledge of the artisan in the field and does not present an inventive concept.
Regarding instant claim 250: In the broadest reasonable interpretation, claim 250 only limits the source of the hESC as being from a genetic library. Claim 250 does not require generation of multiple human hemangio-colony forming cells from different hESCs, but rather still only requires generation of human hemangio-colony forming cells from a single hESC. Any hESC will be necessarily have a unique set of MHC alleles compared to other hESCs which have different MHC alleles. Thus, carrying out the method of copending claim 185, as modified as above, will meet the limitation of instant claim 250.
Regarding instant claims 251-253: Copending claims 199 and 200 teach the hemangio-colony forming cells are differentiated into endothelial and hematopoietic stem cells.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALLISON M FOX whose telephone number is (571)272-2936. The examiner can normally be reached M-F 10-6 EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Christopher Babic can be reached at 571-272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ALLISON M FOX/Primary Examiner, Art Unit 1633