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 .
Status of Claims
Claims 1-18 are pending.
Priority
Claims 1-18 are a 371 of PCT/JP 2022/026062 filed on June 29, 2022, which has priority to foreign applications JAPAN 2022-115115 filed on July 12, 2021, and to JAPAN 2021-187740 filed on November 18, 2021.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on January 10, 2024, and on February 22, 2024, and on November 11, 2024, were filed before the mailing of First Office Action on March 14, 2026. The Non-Patent Literature is in compliance with the provisions of 37 CFR 1.97 and are being considered by the examiner.
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 9 is 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.
Claim 9 recites “a step of dispersing a solid matter obtained in the step of removing the liquid component in an aqueous medium”. As written, this statement is unclear whether claim 9 is referencing the solid matter obtained in step 2 where a mass is obtained or where there is presumably a solid remaining after removing the liquid suspension in step 4.
Claim 1 recites “obtaining a mass containing the extracellular matrix component by removing a solvent through freeze drying treatment after the neutralization step”, and
Claim 1 in “step 4” recites “removing the liquid component from the liquid containing the fragmented extracellular matrix component”
The is further made unclear by the statement “removing the liquid component in an aqueous medium” given that how is the liquid component removed from an aqueous medium. This is especially true if the material is already in a solution. A person of ordinary skill would not be able to determine the metes and bounds of the claimed invention as written.
Claim Rejections - 35 USC § 112
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.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], 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.
Claim 11 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, 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. The triple helix structure is a defining feature given that all collagen types inherently contain a triple-helical structure, and because of this, the language in claim 11 is essentially redundant given that a person of ordinary skill would understand that triple-helical structures are inherently present in collagen. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 1-18 are rejected under 35 U.S.C. §103 as being unpatentable over Song et al. [Preparation and characterization of acellular adipose tissue matrix using a combination of physical and chemical treatments, Mol Med Rep., 2017], in view of Saldin et al. [Extracellular matrix hydrogels from decellularized tissues: structure and function, Acta Biomater., 2016], in view of Fernandez-Perez and Ahearne (Hereinafter Perez) [The impact of decellularization methods of extracellular matrix derived hydrogels, Nature, 2019], in view of Wikipedia [Collagen helix, Wayback Machine Internet Archive, 2020], in view of Mendibil et al. [Tissue-specific decellularization methods: rationale and strategies to achieve regenerative compounds, Molecular Sciences, 2020].
Regarding claim 1, Song et al., discussing methods for deriving decellularized adipose extracellular matrix, teaches a method, e.g. production method, for fragmented extracellular matrix components by determining the extent of decellularization of adipose tissue [Abstract], where the cellular components, including nucleic acids were effectively removed without significant disruption of the morphology or structure of the extracellular matrix [Id.]. After treating with a dissolution solution, the extracellular matrix samples were washed with a neutral buffer to remove reagents and restore physiological condition [Evaluation of decellularization and delipidization ¶ 1]. Furthermore, the samples were then freeze dried where the material appeared similar to a soft porous sponge with “well defined three-dimensional architecture” [Results ¶ 1]. Additionally, lyophilized extracellular matrix is mechanically processed or pulverized for producing smaller extracellular matrix fragments or particles [Evaluation of decellularization and delipidization ¶ 5]. Additionally, Saldin et al, discussing extracellular matrix hydrogels derived from decellularized tissues, discloses the decellularizing mammalian tissue being enzymatically solubilized and then neutralizing to a physiologic pH and temperature [Introduction ¶ 1]. Song et al. also discloses the use of polar solvent extraction of extracellular matrix material as part of tissue processing. Furthermore, a person of ordinary skill would understand that freeze-dried biomaterials are known to resist wetting or uniform suspension, and the use of a polar organic solvent, e.g. ethanol, methanol, acetone, etc., are known to enhance wetting and dispersion, as well as fragmentation and/or solubilization.
For claim 2 where the liquid component is replaced with water after the step of obtaining the liquid and before the step of removing the liquid component, Perez, discussing multiple decellularization methods for extracellular matrix derived hydrogels, discloses that cornea matrices were washed with sterile deionized water for 72 hours following DNAase treatment where the cornea matrices where then dehydrated using a freeze drier [decellularization of porcine corneas part (c) and ¶ 2].
For claim 3 where extracellular matrix was further subjected to ultrasonic crushing treatment after the replacement with water and before the step of removing the liquid, Mendibil et al. discloses that an ultrasonic agitation is as effective at removing cellular materials as an orbital shaker [3.2 Physical methods of decellularization ¶ 4]. Although Mendibil et al. is silent as to when to perform ultrasonication, a person of ordinary skill would understand that ultrasonic crushing or ultrasonication is a well known method for processing biomaterials that include use in methods for decellularizing tissue to isolate the extracellular matrix. Furthermore, a person of ordinary skill would expect enhanced fragmentation and better uniformity of the fragmented extracellular matrix following the use of ultrosonication given that the ultrasonication is being used for its intended purpose. Given this, there is a reasonable expectation of success to combine the teachings of Song et al. with the additional teachings of Saldin et al., along with Perez and Mendibil et al., given that an artisan would expect to use a chemical decellularizing solution followed by some form of neutralizing the decellularizing solution in order to prevent further breakdown of the extracellular matrix where the solution is replaced with a water solution and the mechanically agitated, i.e. ultrasonic crushing, prior to freeze drying where the freeze dried extracellular matrix where the freeze dried extracellular matrix is then resuspended in a polar organic solution that further fragments the extracellular matrix, and lastly, removing the extracellular matrix from the polar organic solution. Therefore, it would have been prima facie obvious to a person of ordinary skill in the art prior to the claimed invention to modify the systems and methods of Song et al. with the additional teachings of Saldin et al., Perez, and Mendibil et al. resulting in a extracellular matrix derived using the method of claims 1-3.
For claim 4 where the neutralized solution is gelled after the neutralization step and before the step of obtaining the mass, Saldin et al. teaches, under the Freytes method, extracellular matrix hydrogels are prepared through neutralization, followed by gelation, and then followed by freeze drying, i.e. lyophilization [Table 1].
For claim 5 where the mass is a porous body, Song et al. teaches that following freeze drying, the material appeared as a soft porous sponge with well defined three-dimensional architecture [Results ¶ 1].
For claim 6 wherein the fragmentation comprises defibration of an extracellular matrix component, Saldin et al. specifically teaches that during decellularization and solubilization processes, the collage fiber structure is disrupted, resulting in loss of the native fiber network [3.2 Gel ultrastructure].
For claim 7 wherein the polar organic solvent in the solution containing the polar organic solvent is 20% v/v to 100% v/v, a person of ordinary skill in the art would test various concentrations of polar organic solvent in order to determine proper solubilization and/or fragmentation of extracellular matrix. The 20% v/v to 100% v/v range represent typical concentrations used in solution processing for extracellular matrix components.
Here, it would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Song et al. with the additional teachings of Saldin et al., Perez, and Mendibil et al. with the further teachings of both Song et al. and Saldin et al. where Saldin et al. teaches the Freytes method that involves extracellular matrix preparation involves neutralization, followed by gelation, and then followed by freeze drying, i.e. lyophilization, while Song et al. discloses that the extracellular matrix can porous in addition. Based on this, there is a reasonable expectation of success that an artisan relying on the teachings of the above references would be able to produce a porous extracellular matrix by following the Freytes method and where the artisan would, through routine optimization, determine the more effective concentration of the polar organic solvent where the concentration levels would be between 20% v/v to 100% v/v.
For claim 8 where the polar organic solution is ethanol, Saldin et al., discussing the Voytik-Harbin method, teaches the use of ethanol [Table 1].
For claim 9 where a step of dispersing a solid matter obtained in the step of removing the liquid component in an aqueous medium, Song et al. discloses removing solvents, i.e. aqueous medium, in order to obtain a dry extracellular matrix mass, followed by dispersing the resulting solid in an aqueous media to form suspensions suitable for downstream applications such as hydrogels and scaffolds [Biochemical composition ¶ 2].
For claim 10 where the extracellular matrix component is collagen, Song et al. discloses that many hydrogels and/or scaffolds have been derived from components of the extracellular matrix, such as collagen, hyaluronic acid and elastin or complex mixtures of extracellular matrix proteins such as Matrigel [Introduction ¶ 2].
For claim 11 where the fragmented extracellular matrix component has a triple helix structure specific to collagen, a person of ordinary skill in the art would understand that a triple helix structure is inherent to collagen given that the structure is formed by three intertwined polypeptide chains where each is adopting a left-handed helical conformation. These left-handed helices then supercoil together to form a right-handed superhelix, creating the triple-helix structure [Wikipedia “Collagen helix” structure].
For claim 12 where cells are mixed with the fragmented extracellular matrix component and then incubated, Song et al. discloses the seeding of cells, specifically hASCs, with the extracellular matrix and then incubating [Human adipose-derived stem cell culture on adipose-derived ECM material ¶ 2].
For claim 13, Song et al. describes extracellular matrix fragmentation that results in fibrous components in the sub-micron to micron scale. Although Song et al. does not specifically disclose the specific sizes limitations in claim 13, a person of ordinary skill would recognize that fragmented extracellular matrix processed via lyophilization or solvent removal will from dried, stacked fibers where the fiber diameter range would fall within the known range for collagen and extracellular matrix fibers post processing.
For claim 14, Saldin et al. discusses the use of SEM images of fully formed extracellular matrix hydrogels showing organized nanofibrous scaffold with interconnecting pores [Gel ultrastructure ¶ 1]. Additionally, it would have been routine and predictable to a person of ordinary skill to measure extracellular matrix distribution in a dried sample. Furthermore, selecting an observed area of 1820 micrometers x 1365 micrometers and reporting 40 to100% coverage is conventional optimization for imaging.
For claim 15 where the fragmented extracellular matrix components are fragmented collagen, Song et al. discloses extracellular matrix that results in fibrous collagen fragments [Generation and characterization of adipose tissue-derived ECM scaffolds].
For claim 16 where the fragmented extracellular matrix component is measured by fluorescence intensity, protein fluorescence assays using ANS are routine in protein chemistry to monitor structural changes. Fragmented extracellular matrix contains proteins, mainly collagen, with exposed hydrophobic regions after fragmentation. It would have been routine to apply ANS fluorescence to monitor fragmented extracellular matrix with a peak within 400 to 500 nm. Furthermore, a person of ordinary skill would find it prima facie obvious to apply known ANS probe to fragmented extracellular matrix to assess structural properties.
For claim 17 where the average length of the fragmented extracellular matrix component is 100 to 400 micrometers, Saldin et al. discloses that extracellular fragment types that range from tens to hundreds of micrometers [Para starting with “Wolf et al. studied”]. Given this, a person of ordinary skill could predictably obtain fragmented extracellular matrix components within the range limitation set forth in claim 17 and would be considered routine optimization.
For claim 18 where the average diameter of the fragmented extracellular matrix components is 10 nm to 10 micrometers, again, Saldin et al. discloses that extracellular fragment types range from tens to hundreds of micrometers [Id.]. A person of ordinary skill in the art would understand this to include diameter as well. Furthermore, a person of ordinary skill would expect that fragmented extracellular matrix components would naturally span this range depending on processing intensity.
The Supreme court has acknowledged:
When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable varition..103 likely bars its patentability…if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond that person’s skill. A court must ask whether the improvement is more than the predictable use of prior-art elements according to their established functions…
…the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results (see KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 U.S. 2007) emphasis added.
In KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court reaffirmed "the conclusion that when a patent 'simply arranges old elements with each performing the same function it had been known to perform' and yields no more than one would expect from such an arrangement, the combination is obvious." Id. at 417 (quoting Sakraida v. Ag Pro, Inc., 425 U.S. 273,282 (1976)). The Supreme Court also emphasized a flexible approach to the obviousness question, stating that the analysis under 35 U.S.C. § 103 "need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418; see also id. at 421 ("A person of ordinary skill is... a person of ordinary creativity, not an automaton.").
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
No claims allowed.
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/JOHN DAVID MOORE/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638