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 .
Formal Matters
Applicant’s claim amendments and arguments in the reply filed on 03 September 2025 are acknowledged and have been fully considered. Claims 20-22, 24-25, 29-33, 35, and 37-44 are pending. Claims 22, 24, 31-33, 35, 37, and 39-44 are under consideration in the instant office action. Claims 20-21, 25, 29-30, and 38 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and/or species, there being no allowable generic or linking claims. Claims 1-19, 23, 26-28, 34, and 36 are cancelled.
Withdrawn Objections/Rejections
Rejections and/or objections not reiterated from the previous office actions are hereby withdrawn as are those rejections and/or objections expressly stated to be withdrawn.
Rejections Maintained
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.
Claim 22 remain 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.
Claims 22 and 40 recite the limitation “the microstructure of the at least one zinc-containing portion…”in line 3 respectively. There is insufficient antecedent basis for this limitation in each of the claims. It should be clear that there is no mention of “microstructure” in claims 22 and 40 before the “the microstructure of the at least one zinc-containing portion…” in claims 22 and 40 respectively.
Response to Arguments
Applicant argues the amendment overcome the rejection.
This is not found persuasive because the amendment did not address the underlying reason for lack of antecedent bases for “microstructure” in claims 22 and 40.
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 22, 24, 31-33, 35, 37, and 39-44 are rejected under 35 U.S.C. 103 as being unpatentable over Tomantschger et al. (US 2016/0038653, previously cited) and O’Brien et al. (US 2010/0008970, previously cited).
Note: The claims are examined as per the elected species of an ultrafine grained structure as zinc microstructure; 70-100% amount of zinc present in the device; elemental zinc as type of zinc; an iron alloy as substrate; zinc is structured as layers on the device; outer layer of polylactic acid and anti-stenosis agents covering the surface of the zinc; vascular stent which is degradable as the type of device.
Applicant Claims
Applicant claims an implantable device comprising the features as claimed.
Determination of the Scope and Content of the Prior Art (MPEP §2141.01)
Tomantschger et al. teach in-vivo biodegradable medical implants, containing at least in part at least partially fine-grained metallic materials provide a strong, tough, stiff and lightweight implant. The in-vivo biodegradable implants are used in a number of stent applications, for fracture fixation, sutures and the like. The in-vivo biodegradable medical implants enable the reduction of implant size and weight and consequently result in reducing the release of implant degradation products into the body (see abstract). This invention relates to biodegradable implants at least partially containing fine-grained metallic materials. A biodegradable medical implant comprises, for example: (a) from 5 to 100% by weight or volume of a metallic material and (b) from 95 to 0% by weight or volume of a polymeric material; where from 5 to 100% of the metallic material has a crystalline microstructure with an average grain size ranging from 2 nm to 10 μm; said implant having a thickness ranging from 5 μm to 2.5 cm; the metallic material, average grain size and thickness being such that the implant degrades entirely in-vivo in a time ranging from one month to twelve months; and/or (a) from 5 to 99% by weight biodegradable polymer or magnesium; (b) from 1 to 95% by weight of a metallic material comprising iron and/or zinc with 5 to 100% by weight of the iron and/or zinc having a crystalline microstructure with an average grain size ranging from 2 nm to 10 μm and having a hardness ranging from 25 to 3,000 VHN, said metallic material comprising iron and/or zinc being present in the form of a coating layer and/or in the form of metallic fillers selected from the group consisting of ribbons, powders, chips, fibers and flakes, said implant having a thickness ranging from 5 μm to 2.5 cm; said thickness being such that the implant degrades entirely in-vivo in a time ranging from one month to twelve months. Preferred metallic materials include iron or iron alloys which are radiopaque although other metals and alloys including zinc-based and/or magnesium-based materials can be used. Pure iron includes “electrolytic pure iron”, defined as containing ≧98% by weight iron, preferably ≧99.5% by weight iron. Preferred iron alloys contain >75% by weight iron, preferably >90% by weight iron and more preferably >95% by weight iron and up to 98% by weight iron. Particularly preferred metallic materials comprise >98% by weight pure metals selected from the group consisting of iron, magnesium and zinc with unavoidable impurities or alloys containing at least 55% by weight of one or more metals selected from the group consisting of iron, magnesium and zinc (see paragraphs 0024-0034). As used herein “at least partially fine-grained” defines a microstructure having an average grain size in the range between 2 nm and 10 microns and includes structures where the grain size is uniform (isotropic microstructure) or non-uniform (anisotropic microstructure) in which case the microstructure varies, e.g., through the cross-section, e.g. by grading and/or layering. Varying the grain size of the metallic deposit can be used to affect a number of properties including the hardness, yield strength, ultimate tensile strength, toughness, Young's modulus, resilience, elastic limit, ductility, internal and residual stress, stiffness, coefficient of friction, electrical conductivity and corrosion resistance including the corrosion rate in bodily fluids. If the microstructure is graded and/or multilayered, at least one section of the metallic material having a thickness of at least 1.5 nm contains isotropic microstructure fine-grained metallic material. Graded and multilayered microstructures, however, can also include amorphous and/or coarse-grained (grain size >10 micron) sections (paragraph 0036). Biodegradable implants according to the invention can be prepared by electroplating suitable metallic compositions onto permanent (becomes part of the implant), or temporary substrates. Suitable permanent substrates include a variety of biodegradable metal substrates such as magnesium-based materials and polymeric substrates. The use of other substrates is envisioned as well, e.g. in the case of implants for use to treat bone fractures, the substrate can comprise bone materials such as apatites and hydroxyapatites, including such materials having a nanocrystalline microstructure. If required, substrates can be metallized to render them sufficiently conductive for plating, e.g., using metallization preferably by a thin layer of iron, zinc or magnesium (paragraph 0082). Suitable biodegradable polymers for use as permanent polymeric substrates or as particulate additions to form metal matrix composites are selected from the group consisting of (i) polyglycolide (PGA), (ii) copolymers such as poly-glycolide-co-trimethylene carbonate (PGA-co-TMC), poly-(D,L-lactide-co-glycolide) (PDLLA-co-PGA), and poly-(L-lactide-co-glycolide) (PLLA-co-PGA); (iii) poly-(L-lactide) (PLLA), poly-(D,L-lactide) (PDLLA), and (v) their stereocopolymers with varying ratios of the L and D,L parts; (vi) polydioxanone (PDS); (vii) trimethylene carbonate (TMC); (viii) polyorthoester (POE); (ix) poly-c-capralacton (PCL); and (x) composite materials comprising one or more of the aforementioned polymers and/or copolymers and PLLA/tricalcium phosphate or PLLA/hydroxyapatite. Suitable fillers for biodegradable polymers include metallic powders, flakes, ribbons and short or long fibers comprising iron, zinc and/or magnesium. The biodegradable metal filler content in the biodegradable filled-polymer ranges from 0% to 90% by weight or volume and provides the desired reinforcement. Preferably, metallic reinforcements have a microstructure which is at least partially fine-grained. Reinforcing polymer based implants with at least partially fine-grained iron, zinc and/or magnesium based fibers using a molding process are possible as the softening/melting temperature of polymers remains much below the temperature inducing grain-growth in at least partially fine-grained metallic materials, which is observed at about half of the melting temperature of the fine-grained metallic material, when expressed in Kelvin (paragraph 0083). In a subsequent step, parts containing the graded and multilayered at least partially fine-grained metallic materials can be subjected to other finishing operations as required including, but not limited to, shaping, perforating, polishing and applying suitable coatings, e.g., containing pharmaceutical drugs. Optionally, pharmaceutically active materials can be incorporated into the entire biodegradable structure to facilitate drug release over the service life of the biodegradable implant (paragraph 0084). It is an objective of the invention to provide biodegradable composite structures comprising a biodegradable polymer and at least in part at least partially fine-grained metallic material, wherein the metallic material is applied as coating to at least part of an external or internal biodegradable polymer substrate surface, as layers, e.g., in biodegradable polymer/metal laminates, or as backbone with the biodegradable polymeric material applied over part or all of the biodegradable metallic structure (paragraph 0047). It is an objective of the invention to provide biodegradable implants, including coronary stents containing fine-grained metallic materials comprising iron and/or zinc with improved mechanical properties manufactured by an electroplating process (paragraph 0056). Biodegradable implants according to the invention can be prepared by electroplating suitable metallic compositions onto permanent (becomes part of the implant), or temporary substrates. Suitable permanent substrates include a variety of biodegradable metal substrates such as magnesium-based materials and polymeric substrates. The use of other substrates is envisioned as well, e.g. in the case of implants for use to treat bone fractures, the substrate can comprise bone materials such as apatites and hydroxyapatites, including such materials having a nanocrystalline microstructure. If required, substrates can be metallized to render them sufficiently conductive for plating, e.g., using metallization preferably by a thin layer of iron, zinc or magnesium (see paragraph 0082). It is an objective of the invention to provide biodegradable and radiopaque biodegradable stents which degrade within one to 12 months or one to 24 months and up to 120 months or 240 months (paragraph 0062). The prior art on biodegradable metallic implants exclusively relies on alloying to achieve the desired biological, chemical and mechanical properties of the implant. Alloying usually requires the introduction of at least small amounts of undesired and potentially toxic elements as, e.g., practiced in current biodegradable magnesium-based implants. In contrast, this invention relates to a suitable refinement and optimization of the microstructure as the preferred approach to vary mechanical properties including the yield strength, toughness and stiffness as well as chemical properties including the bio-corrosion rate. Grain refinement (i.e., Hall-Petch strengthening) substantially enhances mechanical strength thereby reducing the mass/volume of the article. Specifically to biodegradable implants, grain-refinement is therefore considered superior to using alloying as grain-refinement provides lightweight articles with high specific-strength without the introduction of undesired/toxic elements. The bio-corrosion rate is adjusted to the desired level preferably by grain-refinement and/or by chemical composition adjustments (alloying, metal matrix composites, employment of biodegradable polymers). Composite designs of at least partially fine-grained metallic materials and biodegradable polymers are another preferred option including coating biodegradable polymer articles or their precursors with at least partially fine-grained metals/alloys on at least part of the inner or outer surface and/or reinforcing biodegradable polymer articles or their precursors with fibers, ribbons, spines, flakes and powders of at least partially fine-grained metals/alloys (paragraph 0040). A biodegradable medical implant comprising
(a) between 0 to 95% by weight or volume of a biodegradable polymeric material;
(b) a biodegradable metallic material comprising between 5 and 100% by weight or volume of Fe and/or Zn, wherein between 5 and 100% by weight or volume of-the biodegradable metallic material comprises at least one microstructure selected from the group consisting of an amorphous microstructure, a crystalline microstructure with an average grain size range between 2 nm and 500 nm, and a crystalline microstructure with an average grain size range between 500 nm and 1,000 nm; and
said biodegradable medical implant having a maximum in vivo total dissolution time of 120 months (see claim 15).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.012)
Tomantschger et al. do not specifically teach the active agents recited in claim 35 and 43 and the inclusion of gaps, grooves, holes, or cavities on the substrates. These deficiencies are cured by O’Brien.
O’Brien et al. teach drug eluting endoprosthesis devices that comprise a therapeutic agent, see abstract. The stent includes vascular stents, see paragraph [0075]. The stent comprises a corrodible zinc portion (bioerodible metal), see paragraphs [0008]-[0009], [0014],[0041], [0055] and [0060]. The device can comprise overlying layers of different metals with different thicknesses and can each overlie discrete deposits including therapeutic agents of different compositions, see paragraph [0009]. According to O’Brien, in some embodiments the stent includes regions of zinc metal or iron alloy with any of the regions controlling the release of the therapeutic agents, see paragraph [0056] and claims 1-3. The therapeutic active agents of O’Brien include anti-stenotic agents that reduce restenosis, see paragraph [0066]. The device of O’Brien which includes stents is made of materials including stainless steel and thus comprise iron based alloys, see paragraphs [0040] and [0079]. The structural member of the stent includes polylactic acid PLA polymers which can be present in an outer layer on the device covering the metal compounds, see paragraph [0043]. Per Figure 2 C-D, the structural member 30 can include PLA polymer. According to Figure 2D, the drug eluting deposits can comprise a first therapeutic agent 32 and a single overlying layer 38 of bioerodible metal and deposits 33 of a first layer 39 of bioerodible metal and second layer 40 of second bioerodible metal. The overlying layers can be made of zinc metal (elemental zinc) or iron per paragraph [0049]. As can be seen from the figures (e.g. 2C-D) the implantable device can be in contact with the metal compounds which include zinc thus partially covers the surface. Structural member 30 of the stent can be biodegradable, see paragraph [0043]. Since zinc can make up the entire portion of the layer, zinc is present in a zinc containing portion of at least 100% by weight. Regarding claim 23, and a thickness of less than 100nm, O’Brien teaches that the metal particles which include the zinc can be deposited on the stent in a variety of ways which can vary in size to provide different coating features. The process of depositing the metal includes cold gas dynamic spray (CGDS) which O’Brien incorporates by reference to Alkhomev. This method referenced in Alkhomev is used to deposit metal particles of size ranges which include 1 micron, see abstract. Particle sizes of 1-50 microns can provide denser coatings, see Alkhomev. Examiner notes that particles of 1 micron would necessarily have a thickness of greater than 100nm in size, however the thickness of the metal layers is suggested to be an optimizable feature in O’Brien which can be tailored to control the rate of release of the therapeutic agent. According to O’Brien, the thickness of the metal can range up to 200 micrometers, see paragraph [0042]. Adjusting the thickness of the layers controls the release profiles of the therapeutic agents per paragraph [0042]. It would have been obvious to have arrived at the instantly claimed invention as O’Brien suggests iron containing (i.e. stainless steel) stent devices which comprise at least one corrodible zinc portion at a range of about 100% by weight (i.e. one whole layer all containing zinc) that contains a thickness up to 200 microns. With regard to the newly added limitation reciting “wherein the implantable device comprises a substrate, the substrate is provided with gaps, grooves, holes, or cavities and the zinc containing portion is embedded in the gaps, grooves, holes, or cavities.” O’Brien teaches in paragraph 0054 that FIG. 5E depicts an arrangement where the metal structural member 30 includes pores. The therapeutic agent 14 resides within the pores of the metal structural member 30. The bioerodible metal 16 overlies the surface of the metal structural member 30 to prevent the diffusion of the therapeutic agent out of the stent 10 until the bioerodible metal 16 erodes in a physiological environment. The pores can be micropores and/or nanopores. In other embodiments, a substrate may include larger indentations and/or grooves for receiving therapeutic agents. In embodiments where one or more therapeutic agents are deposited within pores, the drug release schedule is controlled both by the erosion rate of the bioerodible metal but also by the slower diffusion of the therapeutic agent out of the porous surface. The pore sizes will impact the rate of diffusion. The therapeutic agent deposited within the pores can be a pure therapeutic agent, a mixture of therapeutic agents, or a mixture that includes inactive ingredients. The therapeutic agent could also be deposited within the pores with a bioerodible polymer that also impacts the kinetic drug release. The therapeutic agent could also be deposited within the pores in the form of a ceramic. This feature of having a therapeutic agent deposited within pores in the surface of a structural member can also be combined with the other features discussed herein.
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the instant invention to incorporate therapeutic agents as recited in claims 35 and 43 because O’Brien et al. teach drug eluting endoprosthesis devices that comprise a therapeutic agent, see abstract. The stent includes vascular stents, see paragraph [0075]. The stent comprises a corrodible zinc portion (bioerodible metal), see paragraphs [0008]-[0009], [0014],[0041], [0055] and [0060]. The device can comprise overlying layers of different metals with different thicknesses and can each overlie discrete deposits including therapeutic agents of different compositions, see paragraph [0009]. One of ordinary skill in the art would have been motivated to do so because according to O’Brien, in some embodiments the stent includes regions of zinc metal or iron alloy with any of the regions controlling the release of the therapeutic agents, see paragraph [0056] and claims 1-3. The therapeutic active agents of O’Brien include anti-stenotic agents that reduce restenosis, see paragraph [0066]. This will provide therapeutic value.
The device of O’Brien which includes stents is made of materials including stainless steel and thus comprise iron based alloys, see paragraphs [0040] and [0079]. The structural member of the stent includes polylactic acid PLA polymers which can be present in an outer layer on the device covering the metal compounds, see paragraph [0043]. Per Figure 2 C-D, the structural member 30 can include PLA polymer. According to Figure 2D, the drug eluting deposits can comprise a first therapeutic agent 32 and a single overlying layer 38 of bioerodible metal and deposits 33 of a first layer 39 of bioerodible metal and second layer 40 of second bioerodible metal. The overlying layers can be made of zinc metal (elemental zinc) or iron per paragraph [0049]. As can be seen from the figures (e.g. 2C-D) the implantable device can be in contact with the metal compounds which include zinc thus partially covers the surface. Structural member 30 of the stent can be biodegradable, see paragraph [0043]. Since zinc can make up the entire portion of the layer, zinc is present in a zinc containing portion of at least 100% by weight. According to O’Brien, the thickness of the metal can range up to 200 micrometers, see paragraph [0042]. Adjusting the thickness of the layers controls the release profiles of the therapeutic agents per paragraph [0042]. With regard to the limitation reciting “wherein the implantable device comprises a substrate, the substrate is provided with gaps, grooves, holes, or cavities and the zinc containing portion is embedded in the gaps, grooves, holes, or cavities.” O’Brien teaches in paragraph 0054 that FIG. 5E depicts an arrangement where the metal structural member 30 includes pores. The therapeutic agent 14 resides within the pores of the metal structural member 30. The bioerodible metal 16 overlies the surface of the metal structural member 30 to prevent the diffusion of the therapeutic agent out of the stent 10 until the bioerodible metal 16 erodes in a physiological environment. The pores can be micropores and/or nanopores. One of ordinary skill in the art would have been motivated to include gaps, grooves, holes, or cavities on the substrate because O’Brien teaches that in other embodiments, a substrate may include larger indentations and/or grooves for receiving therapeutic agents. In embodiments where one or more therapeutic agents are deposited within pores, the drug release schedule is controlled both by the erosion rate of the bioerodible metal but also by the slower diffusion of the therapeutic agent out of the porous surface. The pore sizes will impact the rate of diffusion. The therapeutic agent deposited within the pores can be a pure therapeutic agent, a mixture of therapeutic agents, or a mixture that includes inactive ingredients. The therapeutic agent could also be deposited within the pores with a bioerodible polymer that also impacts the kinetic drug release. The therapeutic agent could also be deposited within the pores in the form of a ceramic. This feature of having a therapeutic agent deposited within pores in the surface of a structural member can also be combined with the other features discussed herein (see paragraph 0054). In the case where the claimed amounts, sizes, thicknesses etc. "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985). Furthermore, differences in concentration or amount will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233,235 (CCPA 1955). One of ordinary skill in the art would have had a reasonable expectation or chance of success combining the teachings of Tomantschger et al. and O’Brien because both references teach stent implants containing biodegradable polyester polymer substrates coated with zinc particles.
In light of the forgoing discussion, one of ordinary skill in the art would have concluded that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed 03 September 2025 have been fully considered but they are not persuasive.
Applicant argues the two types of microstructures taught by Tomantschger are extremely different from "a nano-scale ultrafine-grained structure", "a non- equiaxed crystal structure" and "an equiaxed crystal structure" of the present invention. Tomantschger does not provide any technical inspiration for this application.
The above assertions are not found persuasive because with the broadest reasonable claim interpretation “An implantable device comprising: at least one corrodible zinc-containing portion, wherein the zinc content in the at least one zinc-containing portion is greater than 70% and less than 100% by weight, and the microstructure of the at least one zinc-containing portion is at least one of a non-equiaxed crystal structure, a nano-scale ultrafine-grained crystal structure of less than 100 nm, or an equiaxed crystal structure having a micro-grain size number of 7-14 as measured according to ASTM E112-13 or GB/T 6394-2002.” The at least one zinc-containing portion can be one of the three different alternatives as the features are recited in the alternative. To the minimum, Tomantschger et al. met a nano-scale ultrafine-grained crystal structure of less than 100 nm. Tomantschger et al. teach in-vivo biodegradable medical implants, containing at least in part at least partially fine-grained metallic materials provide a strong, tough, stiff and lightweight implant. The in-vivo biodegradable implants are used in a number of stent applications, for fracture fixation, sutures and the like. The in-vivo biodegradable medical implants enable the reduction of implant size and weight and consequently result in reducing the release of implant degradation products into the body (see abstract). This invention relates to biodegradable implants at least partially containing fine-grained metallic materials. A biodegradable medical implant comprises, for example: (a) from 5 to 100% by weight or volume of a metallic material and (b) from 95 to 0% by weight or volume of a polymeric material; where from 5 to 100% of the metallic material has a crystalline microstructure with an average grain size ranging from 2 nm to 10 μm; said implant having a thickness ranging from 5 μm to 2.5 cm; the metallic material, average grain size and thickness being such that the implant degrades entirely in-vivo in a time ranging from one month to twelve months; and/or (a) from 5 to 99% by weight biodegradable polymer or magnesium; (b) from 1 to 95% by weight of a metallic material comprising iron and/or zinc with 5 to 100% by weight of the iron and/or zinc having a crystalline microstructure with an average grain size ranging from 2 nm to 10 μm and having a hardness ranging from 25 to 3,000 VHN, said metallic material comprising iron and/or zinc being present in the form of a coating layer and/or in the form of metallic fillers selected from the group consisting of ribbons, powders, chips, fibers and flakes, said implant having a thickness ranging from 5 μm to 2.5 cm; said thickness being such that the implant degrades entirely in-vivo in a time ranging from one month to twelve months. Preferred metallic materials include iron or iron alloys which are radiopaque although other metals and alloys including zinc-based and/or magnesium-based materials can be used. Pure iron includes “electrolytic pure iron”, defined as containing ≧98% by weight iron, preferably ≧99.5% by weight iron. Preferred iron alloys contain >75% by weight iron, preferably >90% by weight iron and more preferably >95% by weight iron and up to 98% by weight iron. Particularly preferred metallic materials comprise >98% by weight pure metals selected from the group consisting of iron, magnesium and zinc with unavoidable impurities or alloys containing at least 55% by weight of one or more metals selected from the group consisting of iron, magnesium and zinc (see paragraphs 0024-0034). As used herein “at least partially fine-grained” defines a microstructure having an average grain size in the range between 2 nm and 10 microns and includes structures where the grain size is uniform (isotropic microstructure) or non-uniform (anisotropic microstructure) in which case the microstructure varies, e.g., through the cross-section, e.g. by grading and/or layering. Varying the grain size of the metallic deposit can be used to affect a number of properties including the hardness, yield strength, ultimate tensile strength, toughness, Young's modulus, resilience, elastic limit, ductility, internal and residual stress, stiffness, coefficient of friction, electrical conductivity and corrosion resistance including the corrosion rate in bodily fluids. If the microstructure is graded and/or multilayered, at least one section of the metallic material having a thickness of at least 1.5 nm contains isotropic microstructure fine-grained metallic material. Graded and multilayered microstructures, however, can also include amorphous and/or coarse-grained (grain size >10 micron) sections (paragraph 0036). Biodegradable implants according to the invention can be prepared by electroplating suitable metallic compositions onto permanent (becomes part of the implant), or temporary substrates. Suitable permanent substrates include a variety of biodegradable metal substrates such as magnesium-based materials and polymeric substrates. The use of other substrates is envisioned as well, e.g. in the case of implants for use to treat bone fractures, the substrate can comprise bone materials such as apatites and hydroxyapatites, including such materials having a nanocrystalline microstructure. If required, substrates can be metallized to render them sufficiently conductive for plating, e.g., using metallization preferably by a thin layer of iron, zinc or magnesium (paragraph 0082). Suitable biodegradable polymers for use as permanent polymeric substrates or as particulate additions to form metal matrix composites are selected from the group consisting of (i) polyglycolide (PGA), (ii) copolymers such as poly-glycolide-co-trimethylene carbonate (PGA-co-TMC), poly-(D,L-lactide-co-glycolide) (PDLLA-co-PGA), and poly-(L-lactide-co-glycolide) (PLLA-co-PGA); (iii) poly-(L-lactide) (PLLA), poly-(D,L-lactide) (PDLLA), and (v) their stereocopolymers with varying ratios of the L and D,L parts; (vi) polydioxanone (PDS); (vii) trimethylene carbonate (TMC); (viii) polyorthoester (POE); (ix) poly-c-capralacton (PCL); and (x) composite materials comprising one or more of the aforementioned polymers and/or copolymers and PLLA/tricalcium phosphate or PLLA/hydroxyapatite. Suitable fillers for biodegradable polymers include metallic powders, flakes, ribbons and short or long fibers comprising iron, zinc and/or magnesium. The biodegradable metal filler content in the biodegradable filled-polymer ranges from 0% to 90% by weight or volume and provides the desired reinforcement. Preferably, metallic reinforcements have a microstructure which is at least partially fine-grained. Reinforcing polymer based implants with at least partially fine-grained iron, zinc and/or magnesium based fibers using a molding process are possible as the softening/melting temperature of polymers remains much below the temperature inducing grain-growth in at least partially fine-grained metallic materials, which is observed at about half of the melting temperature of the fine-grained metallic material, when expressed in Kelvin (paragraph 0083). In a subsequent step, parts containing the graded and multilayered at least partially fine-grained metallic materials can be subjected to other finishing operations as required including, but not limited to, shaping, perforating, polishing and applying suitable coatings, e.g., containing pharmaceutical drugs. Optionally, pharmaceutically active materials can be incorporated into the entire biodegradable structure to facilitate drug release over the service life of the biodegradable implant (paragraph 0084). It is an objective of the invention to provide biodegradable composite structures comprising a biodegradable polymer and at least in part at least partially fine-grained metallic material, wherein the metallic material is applied as coating to at least part of an external or internal biodegradable polymer substrate surface, as layers, e.g., in biodegradable polymer/metal laminates, or as backbone with the biodegradable polymeric material applied over part or all of the biodegradable metallic structure (paragraph 0047). It is an objective of the invention to provide biodegradable implants, including coronary stents containing fine-grained metallic materials comprising iron and/or zinc with improved mechanical properties manufactured by an electroplating process (paragraph 0056). Biodegradable implants according to the invention can be prepared by electroplating suitable metallic compositions onto permanent (becomes part of the implant), or temporary substrates. Suitable permanent substrates include a variety of biodegradable metal substrates such as magnesium-based materials and polymeric substrates. The use of other substrates is envisioned as well, e.g. in the case of implants for use to treat bone fractures, the substrate can comprise bone materials such as apatites and hydroxyapatites, including such materials having a nanocrystalline microstructure. If required, substrates can be metallized to render them sufficiently conductive for plating, e.g., using metallization preferably by a thin layer of iron, zinc or magnesium (see paragraph 0082). It is an objective of the invention to provide biodegradable and radiopaque biodegradable stents which degrade within one to 12 months or one to 24 months and up to 120 months or 240 months (paragraph 0062). The prior art on biodegradable metallic implants exclusively relies on alloying to achieve the desired biological, chemical and mechanical properties of the implant. Alloying usually requires the introduction of at least small amounts of undesired and potentially toxic elements as, e.g., practiced in current biodegradable magnesium-based implants. In contrast, this invention relates to a suitable refinement and optimization of the microstructure as the preferred approach to vary mechanical properties including the yield strength, toughness and stiffness as well as chemical properties including the bio-corrosion rate. Grain refinement (i.e., Hall-Petch strengthening) substantially enhances mechanical strength thereby reducing the mass/volume of the article. Specifically to biodegradable implants, grain-refinement is therefore considered superior to using alloying as grain-refinement provides lightweight articles with high specific-strength without the introduction of undesired/toxic elements. The bio-corrosion rate is adjusted to the desired level preferably by grain-refinement and/or by chemical composition adjustments (alloying, metal matrix composites, employment of biodegradable polymers). Composite designs of at least partially fine-grained metallic materials and biodegradable polymers are another preferred option including coating biodegradable polymer articles or their precursors with at least partially fine-grained metals/alloys on at least part of the inner or outer surface and/or reinforcing biodegradable polymer articles or their precursors with fibers, ribbons, spines, flakes and powders of at least partially fine-grained metals/alloys (paragraph 0040). A biodegradable medical implant comprising
(a) between 0 to 95% by weight or volume of a biodegradable polymeric material;
(b) a biodegradable metallic material comprising between 5 and 100% by weight or volume of Fe and/or Zn, wherein between 5 and 100% by weight or volume of-the biodegradable metallic material comprises at least one microstructure selected from the group consisting of an amorphous microstructure, a crystalline microstructure with an average grain size range between 2 nm and 500 nm, and a crystalline microstructure with an average grain size range between 500 nm and 1,000 nm; and
said biodegradable medical implant having a maximum in vivo total dissolution time of 120 months (see claim 15).
Applicant argues the substrate in Tomantschger is a polymer not iron or iron alloys containing metal.
The above assertions are not found persuasive because Biodegradable implants according to the invention can be prepared by electroplating suitable metallic compositions onto permanent (becomes part of the implant), or temporary substrates. Suitable permanent substrates include a variety of biodegradable metal substrates such as magnesium-based materials and polymeric substrates. The use of other substrates is envisioned as well, e.g. in the case of implants for use to treat bone fractures, the substrate can comprise bone materials such as apatites and hydroxyapatites, including such materials having a nanocrystalline microstructure. If required, substrates can be metallized to render them sufficiently conductive for plating, e.g., using metallization preferably by a thin layer of iron, zinc or magnesium (paragraph 0082).
Applicant then argues O’Brien also does not teach the elements described above what Tomantschger alleged to not teach.
The assertions are not found persuasive because first Tomantschger indeed teach the claimed limitations for reasons described above which are incorporated herein by reference. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). O’Brien is added in the rejection to remedy the deficiencies of Tomantschger for not teaching the active agents recited in claim 35 and 43 and the inclusion of gaps, grooves, holes, or cavities on the substrate.
Applicant argues that O’Brien does not teach PLA as outer layer polymer. Applicant also argues O’Brien does not teach the amount of the at least one zinc containing portion.
This is not found persuasive because Tomantschger clearly as described above teach polymer outer layers that lists PLA as a possible polymer and the amount of the at least one zinc containing portion in overlapping manner.
Applicant then argues on combination of O’Brien and Alkhomev. The examiner reminds Applicant that Alkhomev is referenced by O’Brien. The rejection is based on the combination teachings of Tomantschger and O’Brien.
Conclusions
No claims are allowed.
THIS ACTION IS MADE FINAL. 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.
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/TIGABU KASSA/
Primary Examiner, Art Unit 1619