DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after 16 March 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Election/Restriction
Applicant’s election without traverse of collagen II, hyaluronic acid, chondrocytes, and transforming growth factor beta (TGF-b) in the reply filed on 27 July 2026, is acknowledged.
Status of Claims
Claims 1-18 are pending in the instant Office Action.
Claim 11 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Specifically, claim 11 is drawn to an invention in which the bulk polymer crosslinked matrix comprises glycosaminoglycans, which is not the elected collagen II. Election was made without traverse in the reply filed on 27 July 2026.
Claims 1-10 and 12-18 are under consideration in the instant Office Action, to the extent of the following elected species:
the specific bulk polymer crosslinked matrix collagen II;
the specific nanomaterial hyaluronic acid;
the specific mammalian cells chondrocytes; and
the specific active agent transforming growth factor beta (TGF-b).
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy of Finnish parent Application No. FI 20236166, filed on 20 October 2023, has been received from the International Bureau.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 15 October 2024, was filed in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner, with the caveat that the document submitted as Brüggemann et al. (WIPO International Publication No. WO 2016/050357 A1) is actually Brüggemann et al. (U.S. Patent Application Publication No. US 2017/0291361 A1), which belong to the same patent family.
Claim Objections
Claims 2-10 and 12-18 are objected to because of the following informalities:
Claim 2 recites a Markush group of method steps to be performed consisting of two items. The items should be separated by the conjunction “and” rather than a comma (i.e., “a biopsy and a real-time…”, bold added for emphasis).
Claim 3 should be clarified by removing the word “receiving” from line 1 and the phrase “to form the bio-mimetic…” in line 3.
Claim 5 recites a Markush group of parameters, with items being separated by semi-colons. To improve consistency with the other pending claims, claim 5 should be amended to use commas to separate the items. Claim 5 also recites the final item of the Markush group to be monitoring various parameters. Clarity would be improved if the final item in the group recited “monitoring in a printing chamber the light intensity and duration, temperature, humidity, particles, volatile organic compounds (VOC), gas, and weight”.
Claim 13 recites a Markush group comprising three items in line 2. To maintain consistency with the other claims, the penultimate item should be followed by an Oxford comma.
Claim 14 recites a Markush group in lines 2-4. To maintain consistency with the other claims, the penultimate item should be followed by an Oxford comma.
Claim 17 recites “Transforming growth factor beta factors” in line 4. The quoted phrase should be amended to recite “transforming growth factors beta” (bold added for emphasis).
Claim 1 recites “An additive manufacturing method”. Each of claims 2-10 and 12-18 is presented in dependent form and refers directly or indirectly back to claim 1. Dependent claims 2-10 and 12-18, however, each open with the indefinite article “A”. A claim written in dependent form must refer back to and further limit a claim previously set forth. Consistent with that requirement, Office practice is that a dependent claim use the definite article “The” when reciting the same statutory class already introduced in the claim from which it depends. Use of the indefinite article “A” treats the dependent claim as if it were introducing a new, independent method rather than incorporating and further limiting the method already recited in claim 1.
Appropriate correction is required.
Claim Rejections - 35 USC § 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 (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 2-10 and 12-18 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.
The preamble of claim 1 introduces a specific method “An additive manufacturing method”. Claims 2-10 and 12-18 thereafter refer to “A method according to claim…” The indefinite article “A” does not refer back to the method already set forth in claim 1. There is no antecedent basis in claim 1 for a newly introduced “A method”. It is therefore unclear whether each of claims 2-10 and 12-18 further limits the additive manufacturing method already recited in claim 1, as required of a proper dependent claim under 35 U.S.C. 112(d) and 37 CFR 1.75(c), or introduces a different, independent method that merely “accords with” claim 1. The preambles of claims 2-10 and 12-18 also omit “additive manufacturing” which is the statutory class identifier used in claim 1. The omission, combined with the use of “A” rather than “The,” leaves uncertain whether the “method” of claims 2-10 and 12-18 is the same method introduced in the preamble of claim 1.
Claim 4 recites “nanofibers of the nanomaterial” in line 2. There is insufficient antecedent basis for this limitation in the claims because neither claim 4 nor claim 1, from which claim 4 depends, recites nanofibers or a nanomaterial. Claim 3 recites a nanomaterial, but if claim 4 were amended to depend from claim 3, there still would be insufficient antecedent basis for nanofibers. Applicant may overcome this rejection by amending claim 4 to depend from claim 3 and to limit the nanomaterial recited in claim 3 to comprise nanofibers.
Claims 12 and 14 similarly recite “the nanofibers of the nanomaterial”, claim 13 recites “the nanofibers”, and claim 15 recites “the fibers”. There is insufficient basis for these limitations in the claims because claim 1, from which each of claims 12-15 depends, does not recite nanofibers or a nanomaterial. Applicant may overcome the rejection of claims 12-15 by amending the claims to depend from claim 3, to limit the nanomaterial recited in claim 3 to comprise nanofibers, and amending claim 15 to recite “nanofibers” instead of “fibers”.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3-5, 7-10, 12-14, and 16-18 are rejected under 35 U.S.C. 103 as being unpatentable over University of Shanghai for Science and Technology (Chinese Patent Application No. 114120775 A, published on 4 March 2022, provided by Applicant in IDS filed on 15 October 2024, references to English translation, hereafter referred to as USST) as evidenced by Lepage et al. (Tissue Eng. Part B: Reviews 2019, 25 (2), 114.) and Linkhart et al. (Bone 1996, 19 (1), Supplement 1, S1.) in view of Line et al. (Molecular Biology of Cartilage Matrix in Cellular and Molecular Biology of Bone, Ch. 16, Academic Press, 1993, pp. 539-555., hereafter referred to as Line).
USST teaches a biomimetic cell-containing osteochondral scaffold and a method of preparing the scaffold for biomedical tissue engineering (Abstract). The method is taught to comprise extruding multiple layers of bioink atop each other to form a 3D scaffold, which is considered equivalent to the bio-mimetic nanocomposite scaffold printed in one or more layers using a multi-dimensional printer recited in instant claim 1 (claim 1). In Example 1, USST teaches designing a printing program, delivering biological ink to more than one spray head for extrusion, and moving a receiving platform “along the X/Y direction” according to a generated path, which is considered equivalent to generating a bio-mimetic tool path, receiving printable material into one or more printing heads, and dispensing the printable material on a printing surface based on the generated bio-mimetic tool path recited in instant claim 1 and aligning the printing “in a direction of the bio-mimetic tool path” recited in instant claim 4. Further, an osteochondral scaffold is one that is related to articular cartilage and the subchondral bone, as evidenced by Lepage et al., which is considered equivalent to the connective tissue recited in instant claim 1.
The bioinks are taught to comprise stem cells, bone, sacrificial, electrospun, and cartilage materials, and solvents (pg. 3, lines 6-30). The bone, sacrificial, electrospun, and cartilage materials are taught in some embodiments to be collagen (pg. 3, lines 18, 21, 24, and 29) and the cartilage material is taught in one embodiment to be hyaluronic acid (pg. 3, line 29). During the 3D printing process, USST teaches control of printing parameters “known in the field” (pg. 5, lines 8-9, 34-37, and 57-58) to influence the resulting structure, with examples including crosslinking with 405 nm light (Example 2), crosslinking duration (Example 4), temperature (pg. 4, lines 30-31), weight (Example 1), volume (Example 1), and regulating rates of formation (Example 3). In step h. of Example 1, USST teaches crosslinking and curing the printed scaffolds and then placing the scaffolds into a 5% w/w CO environment at 37 °C, which is considered controlling environmental conditions after producing the scaffold as recited in instant claim 7. USST further teaches that the method is carried out under sterile conditions (pg. 4, lines 30-31) and that all materials are sterilized before use (pg. 6, line 27), which is considered equivalent to the sterilization recited in instant claim 8. In some embodiments, USST teaches the printed nanofibers to have diameters of ≤200 nm (pg. 3, line 25) or 100-300 mm (pg. 3, line 27), and to be shaped as a “filament structure” (pg. 3, line 27), which is considered to be equivalent to rod-shaped as recited in instant claim 13. The cartilage layer is taught to be capable of being “perfectly matched with the osteochondral defect part” and the scaffold is taught to be capable of integrating with the human osteochondral tissue structure to promote integrated repair, which is considered equivalent to being oriented in a “wound orientation” as recited in instant claim 14 (pg. 3, lines 36-47). USST additionally teaches that the stem cells in the cartilage layer differentiate into chondrocytes (pg. 6, lines 17-18) and that the scaffold is an articular osteochondral scaffold (pg. 3, line 1). Finally, USST teaches that BMP-2 and BMP-7 proteins are added to their bioink to promote differentiation (pg. 4, lines 45-47, pg. 5, lines 50-51, and Example 1), which both belong to the transforming growth factor beta superfamily as evidenced by Linkhart et al.
USST does not teach the collagen to be type II collagen. This deficiency is offset by the teachings of Line.
Line teaches the molecular biology of the cartilage matrix and its composition, which primarily comprises chondrocytes, collagen type II, hyaluronic acid, aggrecan, and link protein (Title and pg. 540, Introduction, para. 1). Collagen type II is taught to be capable of forming collagen fibrils and to be localized in the hyaline cartilage of articular surfaces, intervertebral disc, retina, sclera, and lens of the eye (pg. 541, Collagen Type II, para. 1-2). Line further teaches that the importance of type II collagen in human development is exemplified by genetic diseases related to coding transcription of the collagen, including lethal developmental diseases, spondyloepiphyseal dysplasia, and Stickler syndrome (pg. 543, Genetic Defects).
It would have been prima facie obvious to a person of ordinary skill in the art, prior to the filing of the instant application, to modify the method of USST to use type II collagen in view of the teachings of Line because the use of a known species within a known genus to impart a known benefit yields predictable results. USST teaches a method of 3D printing a bio-mimetic scaffold using a bioink that comprises collagen, hyaluronic acid, chondrocytes, and members of the transforming growth factor beta superfamily. The method is further taught to use a generated path to produce the osteochondral connective tissue scaffold, to print via more than one printing head in more than one layer, to control parameters during and after printing, to maintain a sterile environment and product, to shape fibers from their bio-ink in filament structures, and to align the fibers of the scaffold to the wound.
In view of the teachings of Line, one of ordinary skill in the art would be motivated to select collagen type II because Line teaches the species to be a primary component of cartilage, which the ordinary artisan would recognize as vital to a scaffold that is related to treatment of articular cartilage and the subchondral bone. Line additionally teaches that type II collagen is important to humans and is localized in cartilage of articular surfaces, which the ordinary artisan would recognize as relevant to the method of USST. Finally, while USST teaches the use of collagen, they do not teach a specific species of collagen and the teachings of Line provide missing information that a person of ordinary skill would require to complete their invention. As a result, there is a reasonable expectation of success in arriving at the method of claims 1, 3-5, 7-10, 12-14, and 16-18 in view of the teachings of USST and Line.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over USST (Chinese Patent Application No. 114120775 A, published on 4 March 2022, provided by Applicant in IDS filed on 15 October 2024, references to English translation) as evidenced by Lepage et al. (Tissue Eng. Part B: Reviews 2019, 25 (2), 114.) and Linkhart et al. (Bone 1996, 19 (1), Supplement 1, S1.) in view of Line (Molecular Biology of Cartilage Matrix in Cellular and Molecular Biology of Bone, Ch. 16, Academic Press, 1993, pp. 539-555) as applied to claims 1, 3-5, 7-10, 12-14, and 16-18 above, and further in view of König et al. (Biomaterials 2005, 26 (5), 495., hereafter referred to as König).
USST and Line have been described above.
USST and Line do not teach generating the printing path using anatomical sectioning following a biopsy or imaging using collagen auto-fluorescence. This deficiency is offset by the teachings of König.
König teaches the imaging of intratissue elastic fibers using multiphoton autofluorescence (Title and Abstract). Collagen and elastin are taught to be “the most important proteins of the connective tissues”, but conventional imaging typically requires invasive removal of tissue (biopsies), slicing with tools, embedding, or other invasive procedures (pg. 495, Introduction, para. 1-2). Both elastin and collagen are taught to be capable of being imaged using blue/green autofluorescence for less invasive imaging, but UV excitation is required which has limited tissue penetration and mutagenic potential (pg. 495, Introduction, para. 3). Utilizing two photon absorption, König was able to non-invasively image collagen and elastin using near-IR light to produce a 3D image of tissue (pg. 495-496, Introduction, para. 4-6 and pg. 499-500, Conclusion).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the filing of the instant application, to combine the teachings of König with the method rendered obvious by the teachings of USST and Line because combining prior art elements according to known methods yields predictable results. The teachings of USST and Line rendered obvious a method of 3D printing a bio-mimetic scaffold using a bioink that comprises type II collagen, hyaluronic acid, chondrocytes, and members of the transforming growth factor beta superfamily. The teachings also rendered obvious the use of a generated path to produce the osteochondral connective tissue scaffold, more than one printing head in more than one layer, control of parameters during and after printing, maintenance of a sterile environment and product, fibers shaped in filament structures, and the alignment of the fibers of the scaffold to wounds.
In view of the teachings of König, a person of ordinary skill in the art would be motivated to generate the printing path using imaging from collagen auto-fluorescence because König teaches the method to be non-invasive and to produce a 3D image of connective tissue, which an ordinary artisan would recognize as useful in their method, particularly when applying the scaffold to human subjects. In addition, while USST teaches the use of a generated path to guide printing, they do not teach the method by which the path is generated, and the teachings of König provide missing information that an ordinary artisan would require to complete their method. As a result, there is a reasonable expectation of success in arriving at the method of instant claim 2 in view of the teachings of USST and Line and further in view of the teachings of König.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over USST (Chinese Patent Application No. 114120775 A, published on 4 March 2022, provided by Applicant in IDS filed on 15 October 2024, references to English translation) as evidenced by Lepage et al. (Tissue Eng. Part B: Reviews 2019, 25 (2), 114.) and Linkhart et al. (Bone 1996, 19 (1), Supplement 1, S1.) in view of Line (Molecular Biology of Cartilage Matrix in Cellular and Molecular Biology of Bone, Ch. 16, Academic Press, 1993, pp. 539-555) as applied to claims 1, 3-5, 7-10, 12-14, and 16-18 above, and further in view of Hourd et al. (Regen. Med. 2015, 10 (7), 863., hereafter referred to as Hourd).
USST and Line have been described above.
USST and Line do not teach configuring the second set of parameters to provide quality control. This deficiency is offset by the teachings of Hourd.
Hourd teaches the impacts of regulatory requirements on 3D-bioprinting (Title and Abstract). With the rising attention focused on 3D bioprinting, Hourd decided to investigate the legislation and regulations that govern 3D bioprinted products in the USA and EU and to understand which challenges “may have significant ramifications under the existing legislation for manufacturers intending to apply computer-aided 3D-bioprinting approaches” (pg. 1, right col., para. 2 - pg. 2, left col., para. 1). Among other regulations, Hourd highlights that good manufacturing practices (GMP) are required for the production of medical devices and that compliance with quality systems is required (pg. 8, right col., penultimate para. and Box 1, pg. 9). Hourd concludes that one parameter that is vital to eventual regulatory compliance is the designation of proper critical to quality attributes (CQAs) such as mechanical stiffness and strength, biocompatibility, and sterility (pg. 10, left col., para. 2 and pg. 17, Conclusion, para. 1).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the filing of the instant application, to combine the teachings of Hourd with the method rendered obvious by the teachings of USST and Line because combining prior art elements according to known methods yields predictable results. The teachings of USST and Line rendered obvious a method of 3D printing a bio-mimetic scaffold using a bioink that comprises type II collagen, hyaluronic acid, chondrocytes, and members of the transforming growth factor beta superfamily. The teachings also rendered obvious the use of a generated path to produce the osteochondral connective tissue scaffold, more than one printing head in more than one layer, control of parameters during and after printing, maintenance of a sterile environment and product, fibers shaped in filament structures, and the alignment of the fibers of the scaffold to wounds.
In view of the teachings of Hourd, a person of ordinary skill in the art would be motivated to configure the parameters of their method to provide quality control because Hourd teaches that compliance with GMP and quality systems is required for 3D bioprinted devices to gain regulatory approval. An ordinary artisan would desire their method to produce devices that comply with legislation and regulations and have high quality and would therefore be motivated to monitor and control production parameters to provide quality control. As a result, there is a reasonable expectation of success in arriving at the method of instant claim 6 in view of the teachings of USST and Line and further in view of the teachings of Hourd.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over USST (Chinese Patent Application No. 114120775 A, published on 4 March 2022, provided by Applicant in IDS filed on 15 October 2024, references to English translation) as evidenced by Lepage et al. (Tissue Eng. Part B: Reviews 2019, 25 (2), 114.) and Linkhart et al. (Bone 1996, 19 (1), Supplement 1, S1.) in view of Line (Molecular Biology of Cartilage Matrix in Cellular and Molecular Biology of Bone, Ch. 16, Academic Press, 1993, pp. 539-555) as applied to claims 1, 3-5, 7-10, 12-14, and 16-18 above, and further in view of Brüggemann et al. (WIPO International Publication No. WO 2016/050357 A1, published on 7 April 2016, provided in the IDS filed on 15 October 2024, hereafter referred to as Brüggemann).
USST and Line have been described above.
USST and Line do not teach the length of the fibers printed. This deficiency is offset by the teachings of Brüggemann.
Brüggemann teaches methods of preparing and orienting biopolymer nanofibers and a composite material comprising the biopolymer nanofibers (Abstract). The nanofibers of the invention are taught to be mixed with a matrix and converted into a “3D printable form” (pg. 4, final para.). The printable material is taught to comprise a natural polymer which in some embodiments is collagen and/or hyaluronan, another name for hyaluronic acid (claims 1-3). Using their method, Brüggemann teaches that the length and diameter of the printed nanofibers is fully controllable via their extrusion setup (pg. 7, numeral 1). The length of the nanofibers is taught to typically be 100 nm to several millimeters, preferably 1 mm to 5 mm (pg. 5, para. 1 and claim 6).
It would have been prima facie obvious to a person of ordinary skill in the art, prior to the filing of the instant application, to modify the method rendered obvious by the teachings of USST and Line to produce fibers of length 1 mm to 5 mm in view of the teachings of Brüggemann because the use of a known technique in a similar method to improve another method in the same manner produces predictable results. The teachings of USST and Line rendered obvious a method of 3D printing a bio-mimetic scaffold using a bioink that comprises type II collagen, hyaluronic acid, chondrocytes, and members of the transforming growth factor beta superfamily. The teachings also rendered obvious the use of a generated path to produce the osteochondral connective tissue scaffold, more than one printing head in more than one layer, control of parameters during and after printing, maintenance of a sterile environment and product, fibers shaped in filament structures, and the alignment of the fibers of the scaffold to wounds.
In view of the teachings of Brüggemann, a person of ordinary skill in the art would be motivated to 3D print the fibers in their method with a length of 1 mm to 5 mm because Brüggemann teaches this range of lengths to be appropriate for nanofiber materials that comprise nanofibers comprising collagen and/or hyaluronic acid, which the ordinary artisan would recognize as relevant to the method rendered obvious above. In addition, neither USST nor Line teach an appropriate length for the nanofibers printed in their method and the teachings of Brüggemann provide missing information that one of ordinary skill would require to complete their method. As a result, there is a reasonable expectation of success in arriving at the invention of claim 15 in view of the teachings of USST and Line and further in view of the teachings of Brüggemann.
Conclusion
No claims are allowed.
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/S.J.S./
Examiner, Art Unit 1619
/TIGABU KASSA/Primary Examiner, Art Unit 1619
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