Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined pursuant to the first inventor to file provisions of the AIA .
DETAILED ACTION
Status of the Claims
The Examiner acknowledges Applicants’ Response filed 24 June 2025. Applicants amended claim 1 therein, and added new claims 18 and 19. Claims 1 – 19 are, therefore, available for substantive examination.
Information Disclosure Statement
The Examiner has considered the Information Disclosure Statement (IDS) filed 11 April 2025, which is now of record in the file.
REJECTIONS WITHDRAWN
Rejections Pursuant to 35 U.S.C. § 103
The obviousness rejection set forth in the Action of 27 March 2025 is hereby withdrawn in light of Applicants’ amendment of the claims, and in favor the new grounds of rejection.
NEW GROUNDS OF REJECTION
Rejections Pursuant to 35 U.S.C. § 112
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(d):
(D) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 5 and 6 are rejected pursuant to 35 U.S.C. § 112(b), as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
Claim 5, dependent from claim 4, recites a limitation directed to “the scaffold body hav[ing] end sides and each of the pores of the scaffold hav[ing] an opening at one of the end sides.” Claim 6, dependent from claim 5, recites a limitation directed to “the pores of the scaffold body [in the form of] passageways extending between at least two of the end sides of the scaffold body.” Claim 4 recites a dependency to claim 1, which claim Applicants have amended to recite that the shape of the scaffold body is “conical,” the shape “being broad at the bottom and narrow at the top.”
It is the Examiner’s position that claims 5 and 6 are indefinite in that one of ordinary skill in the art would be uncertain as to how a conical-shaped implant could have end sides with each of the pores of the scaffold having an opening “at one of the end sides.” Does a conical shape have more than one “end side” to which the pores extend? Given the geometry of a cone, the implant would not be understood to have multiple end sides but, instead, would have a base and an apex, the base possibly being an end side. Absent a geometry that is a variation of a cone, such as a frustumconical shape, it appears to be impossible for the conical implant to have multiple end sides, to one of which the pores extend (claim 5), or the implant to have two end sides between which the pores extend (claim 6).
Appropriate correction or cancelation is required.
Claims 7, 8, 10, and 15 are rejected pursuant to 35 U.S.C. § 112(d), as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Applicants have amended claim 1 to recite that the scaffold body prepared by the claimed method is “in a conical shape being broad at a bottom and narrow at a top.”
Claim 7, dependent from claim 1, recites that the scaffold body “has a cylindrical shape.” A cylindrical shape is not a conical shape. Therefore, the claim is reasonably read as encompassing a shape not recited in claim 1 and, thereby, improperly broadening the scope of the invention.
Claim 8, dependent from claim 1, recites a step in the method of the invention directed to “designing a shape of the scaffold body.” The claim is reasonably interpreted to encompass multiple shapes (“a shape”), rather than being limited to the “conical” shape as recited in claim 1. Consequently, the claim improperly broadens the scope of the invention as recited in claim 1.
Claim 10, ultimately dependent from claim 1, recites a step in the method of the invention directed to “designing a shape of the scaffold body.” The claim is reasonably interpreted to encompass multiple shapes (“a shape”), rather than being limited to the “conical” shape as recited in claim 1. Consequently, the claim improperly broadens the scope of the invention as recited in claim 1.
Claim 15, ultimately dependent from claim 1, recites a step in the method of the invention directed to “designing a shape of the scaffold body.” The claim is reasonably interpreted to encompass multiple shapes (“a shape”), rather than being limited to the “conical” shape, as recited in claim 1. Consequently, the claim improperly broadens the scope of the invention as recited in claim 1.
Applicants may cancel the claims, amend the claims to place the claims in proper dependent form, rewrite the claims in independent form, or present a sufficient showing that the dependent claims comply with the statutory requirements.
Rejections Pursuant to 35 U.S.C. § 103
The following is a quotation of 35 U.S.C. § 103 that 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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 absent any evidence to the contrary. Applicants are advised of the obligation pursuant to 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 – 6 and 8 - 19 are rejected pursuant to 35 U.S.C. § 103, as being obvious over US 2019/0247547 A1 to Le, D. and M. Chen, published 15 August 2019, and claiming priority to 18 October 2016 (“Le ‘547”), in view of Pere, C., et al., International Journal of Pharmaceutics 544: 425 – 432 (2018) (“Pere (2018)”), and Maroulakos, M., et al., Journal of Dentistry 80: 1 – 14 (2019) (“Maroulakos (2019)”).
The Invention As Claimed
Applicants claim a method of generating a dried drug formulation comprising the steps of preparing a substrate to be additively manufactured, wherein the substrate comprises a drug, additive manufacturing the substrate such that a scaffold body is formed of the substrate in a conical shape that is broad at a bottom and narrow at a top, and drying the scaffold body, wherein the additive manufacturing comprises 3D printing the substrate, wherein preparing the substrate comprises generating a printing ink of the substrate suitable for 3D printing, wherein the scaffold body has pores, wherein the scaffold body has end sides and each of the pores of the scaffold has an opening at one of the end sides, wherein the pores of the scaffold body are passageways extending between at least two of the end sides of the scaffold body, wherein the method further comprises gathering drying properties of the specific drying procedure applied when drying the scaffold body, designing a shape of the scaffold body in accordance with the gathered drying properties, and configuring the additive manufacturing of the substrate such that the scaffold body is formed of the substrate in the designed shape, wherein the method further comprises a step of gathering substrate properties of the substrate, wherein the method further comprises designing a shape of the scaffold body in accordance with the gathered substrate properties, and configuring the additive manufacturing of the substrate such the scaffold body is formed of the substrate in the designed shape, wherein the method further comprises selecting a printhead in accordance with the gathered substrate properties, and configuring the additive manufacturing of the substrate such the scaffold body is formed via the selected printhead, wherein the printhead is a pneumatic printhead, a piston printhead, a screw printhead, or an electromagnetic droplet printhead, wherein the method further comprises setting up an aseptic environment, wherein preparing the substrate to be additively manufactured, additive manufacturing the substrate and drying the scaffold body is performed in the aseptic environment, wherein drying the scaffold body is lyophilizing the scaffold body, wherein the method further comprises gathering lyophilization properties of the specific lyophilization procedure applied when lyophilizing the scaffold body, designing a shape of the scaffold body in accordance with the gathered lyophilization properties, and configuring the additive manufacturing of the substrate such that the scaffold body is formed of the substrate in the designed shape, wherein the substrate is additive manufactured onto a freezing member such that the scaffold body is frozenly formed, wherein the drug comprises a protein, wherein the protein is an antibody, and wherein the method further comprises a step of providing the dried scaffold body as drug substance which involves a step of packaging the dried scaffold body.
The Teachings of the Cited Art
Le ‘547 discloses a hydrogel comprising a porous structure of ordered structural elements, wherein said structural elements comprises crosslinked hyaluronic acid (HA) (see Abstract), wherein the crosslinked hydrogel is in the form of biocompatible scaffolds with a well-defined, homogeneous 3D structure and porous network (see ¶[0006]), wherein the hyaluronic acid is crosslinked with divinyl sulfone (DYS), carbodiimide, or adipic acid dehydrate (see ¶[0004]), wherein the hydrogel farther comprises at least one additional component, for example, a biologically active agent such as a protein (see ¶[0020]), wherein the crosslinked hydrogel is prepared by mixing HA, DVS, and a solvent to obtain a mixture [a printing ink], depositing said solution onto a cooled substrate to obtain a frozen construct [scaffold], and contacting (or immersing) said frozen construct with an alkaline solution at a temperature below the freezing point of the construct to cross-link HA with DVS, to obtain a cross-linked hydrogel (see ¶¶[0024] – [0026]), wherein the hydrogel construct is three-dimensional (see ¶[0034]), wherein the solution is deposited using a device comprising a motor-driven nozzle, or using fused deposition modelling (FDM) (see ¶[0044]), wherein the crosslinked hyaluronic acid hydrogel constructs have a well-defined geometry and an ordered structure allowing the production of more complex 3D hydrogels (see ¶[0089]), wherein the constructs comprise at least one layer comprising or consists of ordered structural elements, and preferably multiple layers (see ¶[0093]), wherein the ordered structural elements form a hierarchical structure, such as a 3D hierarchical scaffold (see ¶[0094]), wherein the porous structure of the scaffolds comprises interconnected pores (see ¶[0095]), wherein the scaffold has the shape of a mat, a sheet, a cube, a cuboid, a sphere, an ellipsoid, a prism, or a cylinder (see ¶[0119]), wherein the hydrogel constructs are applied for medical use and/or therapy (see ¶[0121]), wherein the hydrogel scaffolds have the shape of an anatomical structure generated from medical 3D imaging data for example CT, MRI, or ultrasound (see ¶[0122]), wherein the disclosed methods allow for the production of 3D hydrogels that possess proper shape, dimensions, porosity and physical properties suitable for cell attachment and subsequent tissue development (see ¶[0126]), wherein the HA-DVS solution is deposited onto a substrate to obtain the three-dimensional construct that changes into a solid form when it is deposited onto the cooled substrate, bringing the HA-DVS solution to a temperature below its melting point during and/or after it has been deposited onto the substrate to solidify the solution and create a construct that is dimensionally stabilized (see ¶[0173]), wherein the constructs are produced by extruding small strings or filaments of the solution to form layers as the solution solidifies immediately after extrusion from, for example, a nozzle [print head] (see ¶[0180]), wherein the HA-DVS solution can be deposited, extruded or printed onto the substrate by fused deposition modelling (FDM), an additive manufacturing (AM) technology commonly used for modelling, prototyping, and production applications, wherein the HA-DVS solution is dispensed on a cooled substrate onto which it will solidify (see ¶[0183]), wherein the HA-DVS solution is dispensed through a nozzle that follows a tool-path controlled by a computer-aided manufacturing (CAM) software package, and the construct is built from the bottom up, one layer at a time, to create scaffolds with dimensions and shapes defined by a CAD drawing that controls the path of the 3D printer (see ¶[0184]), wherein the scaffolds comprise components such as lectins, antibodies, antibody fragments, his-tagged proteins, lys-tagged proteins, positively charged proteins, methylated collagen and derivatives thereof (see ¶[0225]), and wherein, in specific embodiments, the crosslinked HA constructs are lyophilized for 96 hours and subsequently stored in a dessicator at room temperature (see ¶[0302]). The reference does not explicitly disclose a substrate with a scaffold body in a conical shape, or processes that comprise “gathering” of properties of the various method steps in order the fabricate a scaffold construct according to those properties. The teachings of Pere (2018) and Maroulakos (2019) remedy those deficiencies.
Pere (2018) discloses polymeric microneedle (MN) patches fabricated by stereolithography, a 3D printing technique, for the transdermal delivery of insulin, wherein biocompatible resin was photopolymerized to build pyramidal and conical microneedle designs followed by inkjet print coating of insulin formulations (see Abstract; see also, Fig. 1B), wherein the force required to pierce the skin has been found to be straightforwardly affected by the geometry of the MN’s (see p. 426, 2nd col., 6th para.), wherein the conical design requires the least force to penetrate the porcine skin, the variation of the maximum load required for penetration being attributed to the difference of the MN-to-skin contact area between the two designs (see p. 430, 1st col., 2nd para.), and wherein the 21% difference in area between the two designs indicates that the frictional forces after initial penetration until the threshold force in reached, are greater for the pyramidal needles than for the conical needles (see p. 430, 2nd col., 2nd para.).
Maroulakos (2019) discloses three-dimensional bioprinting methods for construction of 3D volumetric structures (see Abstract), wherein 3D printing technologies involve building a well-defined 3D structure from a computer-aided design (CAD) model using layer by layer arrays based on information collected by medical imaging technology, such as computed tomography (CT) and magnetic resonance imaging (MRI), wherein the acquired raw imaging data are processed and reconstructed as a volumetric model, which is then transmitted to a 3D bioprinter system, and 3D structures are produced using computer-aided manufacturing (CAM) tools, based on anatomical information of the tissue to be regenerated or reconstructed, yielding layered biological materials, with custom-made external shape and internal porosity (see p. 1, 2nd col., 2nd para. – p. 2, 1st col., 1st para.), wherein a variety of bioprinters are available for such processors (see Fig. 1, p. 2; see also Table 1), wherein several parameters of scaffold design are important to fulfill bone in-growth, including scaffold macro-geometry, so that the scaffold precisely fits in the bone defect without having a complicated outline to be printable by 3D printing; the micro-architecture of the scaffold should be well-structured and with sufficient porosity and interconnectivity for bone in-growth, cell transportation and nutrient diffusion; the scaffold should be bioactive by incorporation of mineral phases for osteoinductivity (chemical binders to create a mineralized structure that can house cells), and mechanical properties should be analogous to native bone, wherein the selection of the biomaterial being driven by the size and load-bearing demands of the affected site (see p. 10, 2nd col., 4th para.), and wherein 3D printing technology enables the meticulous study, design, fabrication and surgical positioning of the scaffold/implant, also providing for virtual planning with fewer surgical steps, minimizing operative and postsurgical complications (see p. 11, 2nd col., 3rd para.).
Application of the Cited Art to the Claims
It would have been prima facie obvious before the filing date of the claimed invention to prepare porous structures of ordered structural elements comprising crosslinked hyaluronic acid (HA) hydrogel in the form of biocompatible scaffolds with a well-defined, homogeneous 3D structure and porous network, wherein the hydrogel farther comprises at least one additional component, for example, a biologically active agent such as a protein, such as an antibody or an antibody fragment, wherein the crosslinked hydrogel is prepared by mixing HA, DVS, and a solvent to obtain a mixture [a printing ink], depositing the solution onto a cooled substrate to obtain a frozen construct [scaffold], and contacting (or immersing) the frozen construct with an alkaline solution at a temperature below the freezing point of the construct to cross-link HA with DVS, to obtain a 3D cross-linked hydrogel construct, wherein the solution is deposited using a device comprising a motor-driven nozzle, or using fused deposition modelling (FDM), wherein the constructs comprise at least one layer comprising or consists of ordered structural elements, and preferably multiple layers, wherein the ordered structural elements form a 3D hierarchical scaffold, wherein the porous structure of the scaffolds comprises interconnected pores, wherein the scaffold has the shape of a cylinder, wherein the hydrogel scaffolds have the shape of an anatomical structure generated from medical 3D imaging data, for example CT, MRI, or ultrasound, wherein the HA-DVS solution can be deposited, extruded, or printed onto the substrate by fused deposition modelling (FDM), an additive manufacturing (AM) technology, wherein the HA-DVS solution is dispensed through a nozzle that follows a tool-path controlled by a computer-aided manufacturing (CAM) software package, and the construct is built from the bottom up, one layer at a time, to create scaffolds with dimensions and shapes defined by a CAD drawing that controls the path of the 3D printer, and wherein, in specific embodiments, the crosslinked HA constructs are lyophilized for 96 hours and subsequently stored in a dessicator at room temperature, as taught by Le ‘547, wherein the scaffolds are fabricated by stereolithography in a conical form, as taught by Pere (2018), and wherein acquired raw imaging data are processed and reconstructed as a volumetric model, which is then transmitted to a 3D bioprinter system, and 3D structures are produced using computer-aided manufacturing (CAM) tools, based on anatomical information of the tissue to be regenerated or reconstructed, yielding layered biological materials, with custom-made external shape and internal porosity, wherein several parameters of scaffold design are important to fulfill bone in-growth, including scaffold macro-geometry, so that the scaffold precisely fits in the bone defect without having a complicated outline to be printable by 3D printing; the micro-architecture of the scaffold should be well-structured and with sufficient porosity and interconnectivity for bone in-growth, cell transportation and nutrient diffusion; the scaffold should be bioactive by incorporation of mineral phases for osteoinductivity (chemical binders to create a mineralized structure that can house cells), and mechanical properties should be analogous to native bone, wherein the selection of the biomaterial being driven by the size and load-bearing demands of the affected site (see p. 10, 2nd col., 4th para.), and wherein 3D printing technology enables the meticulous study, design, fabrication and surgical positioning of the scaffold/implant, also providing for virtual planning with fewer surgical steps, minimizing operative and postsurgical complications, as taught by Maroulakos (2019). One of skill in the art would be motivated to do so, with a reasonable expectation of success in so doing, by the teachings of Pere (2018) to the effect that a conical shape requires less insertion force when used to deliver a pharmacologically active ingredient to a patient’s skin, and by the teachings of Maroulakos (2019), to the effect that 3D printing technology enables the meticulous study, design, fabrication and surgical positioning of the scaffold/implant, also providing for virtual planning with fewer surgical steps, minimizing operative and postsurgical complications.
The Examiner notes that claims 8, 9, and 15 recite multiple process steps involving the “gathering” of properties [information?] for use in planning and/or executing various steps in the design and manufacturing of 3D printed scaffolds. It is the Examiner’s position that the references disclose multipole processes involving data generation relating to the design and execution of 3D printed scaffolds, although none of these processes are characterized as “gathering,” and that these processes would read on the gathering limitations.
With respect to claims 5 and 6, which claims recite limitations directed to pore characteristics, the Examiner notes that the cited references do not address porosity characteristics using the recited terms. However, the Examiner further notes that the cited references disclose porous scaffold constructs with interconnected pores, and that Maroulakos (2019) specifically addresses the porosity needed to allow influx of cells and growth factors into the pores of the scaffolds. As for claim 6, which claim recites that the pores extend between the end sides of the implant structures, it is the Examiner’s position that the references disclose scaffolds with porosity that necessarily extends to the outer surfaces (ends) of the scaffolds, as required to allow access to the interior voids of the scaffolds of cells and other components, thus reading on the limitations recited in claims 5 and 6.
With respect to the limitation recited in claims 11 and 12 directed to print head choices for 3D printers used in the methods of the invention, the Examiner notes that Maroulakos (2019) illustrates multiple nozzle/print head designs that are used in bioprinting that would read on these limitations.
With respect to claim 13, which claim recites a limitation directed to aseptic conditions under which the printing would be performed, the Examiner notes that the cited references do not address such conditions. However, both of the references disclose the 3D printing of implants for surgical bone repair. It is the Examiner’s position that one of ordinary skill in the art would appreciate that maintenance of aseptic conditions is standard, and required, in all surgeries, including those for implantation of scaffolds in bone repair.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by claims 1 - 19 would have been obvious within the meaning of 35 USC § 103.
Response to Applicants’ Arguments
The Examiner has considered the arguments offered by Applicants in their Response filed 24 June 2025, but does not find them persuasive. The primary argument of Applicants is that the cited references do not disclose the formation of scaffolds with a conical shape, and that such shape provides for “an improved heat flow,” that, presumably, facilitates drying. The Examiner acknowledges that the cited references do not expressly address factors such as drying processes in relation to implant geometry. However, the fact that Applicants have recognized another advantage that would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). The reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006).
NO CLAIM IS ALLOWED.
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.
CONCLUSION
Any inquiry concerning this communication or any other communications from the Examiner should be directed to Daniel F. Coughlin whose telephone number is (571)270-3748. The Examiner can normally be reached on M - F 8:30 a.m. - 5:00 p.m.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner’s supervisor, David Blanchard, can be reached on (571)272-0827. The fax phone number for the organization where this application or proceeding is assigned is (571)273-8300.
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/DANIEL F COUGHLIN/
Examiner, Art Unit 1619
/DAVID J BLANCHARD/ Supervisory Patent Examiner, Art Unit 1619