DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s response (amendments and arguments), is acknowledged. Applicant’s arguments have been fully considered but are not yet persuasive in light of the new amendments which have triggered the new, modified rejections below. After amendment, claims 172, 174, 175, 179-194 remain pending and are examined on the merits.
See Interview Summary attached, discussing the amendments triggering new modified issues/rejections addressed below on the record.
The examiner remains open to further interview to advance prosecution on the merits.
Election/Restrictions – Species Elections, Without Traverse, Maintained
Applicant’s election without traverse of peptide SEQ ID NO: 434 and the other elements set forth in the reply filed on 12/12/24 is acknowledged.
Allowable Subject Matter – Peptide SEQ ID NOS: 433 & 434 (Elected), Previously Noted
The examiner offers applicant a complete product (once fully claimed) comprising peptide SEQ ID NO: 433 as found both novel and inventive by the U.S. International Authority examiner in the related PCT application (*disposition below) and by extension this U.S. examiner now in the National Stage phase of prosecution on the merits of the instant subject matter, extends the same offer equally as well as to elected peptide SEQ ID NO: 434 not found reasonably taught or suggested based on the prior art of record. WO 2010044758 is deemed the closest prior art of record as also identified by the U.S. International Authority examiner (see below).
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Claim Rejections - 35 USC § 112(a)(i)/(pre-AIA ) – Written Description, Modified,
Necessitated by Amendment
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.
Claims 172, 174, 175, 179-194 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.
To provide evidence of possession of a claimed genus, the specification must provide sufficient distinguishing/identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof.
COAT[ING] – NOW GENERALLY, POSITIVELY AMENDED INTO CLAIMS
The newly added element/limiting - coat[ing] – is claimed at full breadth without any limitation based on representative examples and/or support to confer the organic peptide(s) the ability to 'non-covalently bond' to any form - including hardened forms - of the inorganic 3D structure comprising the combination of ceramic and polymer. At issue is what is required in the 'coat[ing]' to allow the BMP peptide to non-covalently bond to the ceramic/polymer in any formation? The specification provides the following support (see U.S. Patent Publication No. 20220323641):
[0101] The 3D-printed structures described herein are coated with a tetherable protein (for example, tBMP2) during fabrication that promotes bone growth. In some instances, the 3D-printed structures can be seeded with cells post-fabrication such that the cells occupy the pores of the 3D-printed structure. Once prepared, the 3D-printed structures can be surgically implanted into a patient for surgical bone replacement and grafting.
[0141] The trisolvent blend with varied vapor pressures enables initial hardening of the printed filaments of the calcium phosphate-polymer ink 220 that are extruded from the printer 230, as the high volatility dichloromethane evaporates first. The two lower volatility solvents (2-butoxyethanol and dibutyl phthalate) slow the precipitation of the dissolved PCL binder, allowing it to coat the β-TCP powder and neck between adjacent particles while also creating an interconnected porous network. Additionally, the lower volatility solvents remain in the printed structure 235 for some time, which facilitates fusing of a printed filament to adjacent 3D-printed filaments (either beside of or on top of the previously extruded filament).
[0156] Any of the 3D-printed implantable structures 160, 260, 360 described herein can then be coated with a tetherable protein (for example, tBMP2) as part of the treatment of the 3D implantable structures (steps 176, 276, 376). Following completion of the implantable structures using any of the methods discussed above, the implantable structures can then be washed in an acidic sodium acetate buffer. This can be one, two, or more washes. The washing can then be followed by a two-hour incubation of the 3D-implantable structures in sodium acetate buffer that contains a 1 mg/mL concentration of tBMP2 protein. The tetherable tBMP2 binds to the β-TCP surface of the implantable structures in a monolayer.
[0157] In some embodiments, a bone putty (rather than a 3D-printed component) is used to deliver tetherable tBMP2 to a bone regeneration site. A putty material can be roughly shaped by hand into the shape and size of the bone void and inserted into the cavity where bone regeneration is desired. A sodium carboxymethylcellulose (CMC) hydrogel can be mixed with β-TCP granules that have been coated with tBMP2 to create a bone void-filling putty. A putty of 50 wt % β-TCP (coated with tBMP2) and 50 wt % sodium CMC hydrogel can be formulated with asymmetric centrifugal mixing. To make a 6 wt % sodium CMC hydrogel, 10.5 g of deionized water is placed in a polypropylene container and 0.9 g of sodium CMC powder is added to the water. The material is mixed in a FlackTek Speedmixer at 3500 rpm for 10-11 minutes to fully dissolve the sodium carboxymethylcellulose powder and the resulting material is an extremely viscous gel. After that, 3.6 g of additional deionized water is added to dilute the thick gel and mixed at 3500 rpm for 2 minutes. Fifteen grams of β-TCP granules (250 μm-1000 μm, previously coated with tBMP2) are then added in stepwise increments (e.g., 5 g, 5 g, 5 g) followed by mixing at 2500 rpm for 1 min after each granule addition. A final mixing step of 3500 rpm for 2 min is done to fully homogenize the putty (asymmetric centrifugal mixing). The β-TCP particles are coated with tBMP2 before mixing the β-TCP granules into the hydrogel
The breadth and scope of the claims would have to be amended based on the support in possession (to satisfy 35 USC 112(a) written description).
The above is necessitated by amendment, following related relevant issues previously identified and retained for relevant/continuity here:
In this case, as previously stated, the genus claimed and specification (e.g. para 35) are open to the BMP peptide being bound in any way to the ceramic-polymer 3D structure, yet the specification species (e.g. para 193) may only support ‘coating’ such, e.g. the BMP peptide surface-coating upon the intermediate ceramic-polymer 3D structure. Possession appears lacking based on support being incomplete as omitting essential steps, elements, and/or structural cooperative relationship connections between the BMP peptide and the 3D structure elements (ceramic and polymer) and how all 3 fit together like a puzzle as a final end-product structure rending the current claim scope leaving omissions amounting to a gap between the steps. See MPEP § 2172.01. For instance para 35 and 193 simultaneously leave open and/or narrow (coating only) that the BMP peptide is simply a ‘coating’ over 3D structure comprising routinely optimizable ratios of ceramic to polymer. However, the metes and bounds of the claims are indefinite as currently claims as elements/structural cooperative relationship thereof do not convey such to PHOSITA. See e.g. para 35 and 193, especially last sentence below:
[0035] In embodiments, the method further comprises combining the three-dimensional structure with a therapeutic agent. In the method, the therapeutic agent may comprise a mammalian growth factor or a functional portion thereof and/or one or more polypeptides selected from Table 4, or a functional portion thereof. The therapeutic agent may comprise a bone morphogenetic protein (BMP).
[0193] [ ] (7) A three-dimensional implantable object comprising an ink of any of the previous embodiments. (8) The object of embodiment 7, wherein the object is a porous scaffold comprising a plurality of layers, each layer comprising the ink. (9) A method of treating a subject having a tissue defect, the method comprising: surgically implanting the three-dimensional object of embodiment 7 into the tissue defect of the subject, thereby treating the subject. (10) A method of manufacturing an ink for three-dimensional printing, the method comprising: preparing a liquid solution; combining the liquid solution with a portion of calcium phosphate ceramic (β-TCP) or HA particles; and mixing the liquid solution and β-TCP particles via centrifugal mixing. (11) The method of embodiment 10, comprising combining the polymeric solution with a dispersing agent and an antifoaming agent. (12) The method of embodiment 10, comprising combining at least an additional portion of β-TCP or HA particles and repeating the mixing steps at least once. (13) The method of embodiment 10, comprising ensuring that all the β-TCP or hydroxyapatite particles are wet by the liquid solution. (14) A method of preparing a three-dimensional printed implanted object, the method comprising: printing a printed structure using the ink of embodiment 10; drying the printed structure; and heat-treating the printed structure. (15) [ ] The method of embodiment 14, further comprising coating the printed structure with a tetherable protein by soaking the printed structure in a tBMP2 solution. (18)
As such, until the claim scope is amended commensurate in scope to reflect the issues identified above, a reasonable complete search of the intended claimed invention is not presently possible, not knowing how the BMP peptide is to be bound/attached to the ceramic and polymer.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111; clearly states that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry,whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116).
With the exception of the BMP peptide coatings supported for non-covalently binding the ceramic-polymer 3D structure, the skilled artisan cannot envision the detailed chemical structure of the encompassed variants, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF's were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovinesequence. Here, applicant may have only provided that the BMP peptide ‘coats’ the ceramic-polymer 3D structure and is not internally bonded therewith, but has not claimed the coating that achieves such (properties, elements thereto).
Therefore, the full breadth of the claims are not presently deemed to have been in Applicant’s ‘possession’ and found to meet the written description provision of 35 U.S.C. §112.
Claim Rejections - 35 USC § 112(b) – Indefiniteness, Modified, Necessitated by Amendment
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.
Claims 172, 174, 175, 179-194 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.
All the claims are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential steps, elements, and/or structural cooperative relationship connections between the newly amended ‘coat[ing]’ allowing the BMP peptide to non-covalently attach to the 3D structure elements (ceramic and polymer) and how all 3 fit together like a puzzle as a final end-product structure rending the current claim scope leaving omissions amounting to a gap between the steps. See MPEP § 2172.01. For instance para 35 and 193 simultaneously leave open and/or narrow (coating only) that the BMP peptide is simply a ‘coating’ over 3D structure comprising routinely optimizable ratios of ceramic to polymer. At issue is what is required in the 'coat[ing]' to allow the BMP peptide to non-covalently bond to the ceramic/polymer in any formation? However, the metes and bounds of the claims are indefinite as currently claims as elements/structural cooperative relationship thereof do not convey such to PHOSITA. See U.S. Patent Publication No. 20220323641:
[0101] The 3D-printed structures described herein are coated with a tetherable protein (for example, tBMP2) during fabrication that promotes bone growth. In some instances, the 3D-printed structures can be seeded with cells post-fabrication such that the cells occupy the pores of the 3D-printed structure. Once prepared, the 3D-printed structures can be surgically implanted into a patient for surgical bone replacement and grafting.
[0141] The trisolvent blend with varied vapor pressures enables initial hardening of the printed filaments of the calcium phosphate-polymer ink 220 that are extruded from the printer 230, as the high volatility dichloromethane evaporates first. The two lower volatility solvents (2-butoxyethanol and dibutyl phthalate) slow the precipitation of the dissolved PCL binder, allowing it to coat the β-TCP powder and neck between adjacent particles while also creating an interconnected porous network. Additionally, the lower volatility solvents remain in the printed structure 235 for some time, which facilitates fusing of a printed filament to adjacent 3D-printed filaments (either beside of or on top of the previously extruded filament).
[0156] Any of the 3D-printed implantable structures 160, 260, 360 described herein can then be coated with a tetherable protein (for example, tBMP2) as part of the treatment of the 3D implantable structures (steps 176, 276, 376). Following completion of the implantable structures using any of the methods discussed above, the implantable structures can then be washed in an acidic sodium acetate buffer. This can be one, two, or more washes. The washing can then be followed by a two-hour incubation of the 3D-implantable structures in sodium acetate buffer that contains a 1 mg/mL concentration of tBMP2 protein. The tetherable tBMP2 binds to the β-TCP surface of the implantable structures in a monolayer.
[0157] In some embodiments, a bone putty (rather than a 3D-printed component) is used to deliver tetherable tBMP2 to a bone regeneration site. A putty material can be roughly shaped by hand into the shape and size of the bone void and inserted into the cavity where bone regeneration is desired. A sodium carboxymethylcellulose (CMC) hydrogel can be mixed with β-TCP granules that have been coated with tBMP2 to create a bone void-filling putty. A putty of 50 wt % β-TCP (coated with tBMP2) and 50 wt % sodium CMC hydrogel can be formulated with asymmetric centrifugal mixing. To make a 6 wt % sodium CMC hydrogel, 10.5 g of deionized water is placed in a polypropylene container and 0.9 g of sodium CMC powder is added to the water. The material is mixed in a FlackTek Speedmixer at 3500 rpm for 10-11 minutes to fully dissolve the sodium carboxymethylcellulose powder and the resulting material is an extremely viscous gel. After that, 3.6 g of additional deionized water is added to dilute the thick gel and mixed at 3500 rpm for 2 minutes. Fifteen grams of β-TCP granules (250 μm-1000 μm, previously coated with tBMP2) are then added in stepwise increments (e.g., 5 g, 5 g, 5 g) followed by mixing at 2500 rpm for 1 min after each granule addition. A final mixing step of 3500 rpm for 2 min is done to fully homogenize the putty (asymmetric centrifugal mixing). The β-TCP particles are coated with tBMP2 before mixing the β-TCP granules into the hydrogel
See also e.g. para 35 and 193, especially last sentence below:
[0035] In embodiments, the method further comprises combining the three-dimensional structure with a therapeutic agent. In the method, the therapeutic agent may comprise a mammalian growth factor or a functional portion thereof and/or one or more polypeptides selected from Table 4, or a functional portion thereof. The therapeutic agent may comprise a bone morphogenetic protein (BMP).
[0193] [ ] (7) A three-dimensional implantable object comprising an ink of any of the previous embodiments. (8) The object of embodiment 7, wherein the object is a porous scaffold comprising a plurality of layers, each layer comprising the ink. (9) A method of treating a subject having a tissue defect, the method comprising: surgically implanting the three-dimensional object of embodiment 7 into the tissue defect of the subject, thereby treating the subject. (10) A method of manufacturing an ink for three-dimensional printing, the method comprising: preparing a liquid solution; combining the liquid solution with a portion of calcium phosphate ceramic (β-TCP) or HA particles; and mixing the liquid solution and β-TCP particles via centrifugal mixing. (11) The method of embodiment 10, comprising combining the polymeric solution with a dispersing agent and an antifoaming agent. (12) The method of embodiment 10, comprising combining at least an additional portion of β-TCP or HA particles and repeating the mixing steps at least once. (13) The method of embodiment 10, comprising ensuring that all the β-TCP or hydroxyapatite particles are wet by the liquid solution. (14) A method of preparing a three-dimensional printed implanted object, the method comprising: printing a printed structure using the ink of embodiment 10; drying the printed structure; and heat-treating the printed structure. (15) [ ] The method of embodiment 14, further comprising coating the printed structure with a tetherable protein by soaking the printed structure in a tBMP2 solution. (18)
As such, until the claim scope is amended commensurate in scope to reflect the issues identified above, a reasonable complete search of the intended claimed invention is not presently possible, not knowing what properties in the ‘coat[ing]’ must be positively claimed in order for the BMP peptide to non-covalently bond to the ceramic and polymer.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. 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 nonprovisional extension fee (37 CFR 1.17(a)) 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 mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MAURY AUDET whose telephone number is (571)272-0960. The examiner can normally be reached on M-Th. 7AM-5:30PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko Garyu can be reached on 571-272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
/MAURY A AUDET/Primary Examiner, Art Unit 1654
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