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 .
Election/Restrictions
Applicant’s election with traverse of Group I (Claims 1-15; drawn to a method of producing a particulated tissue) in the reply filed on November 5, 2024, is acknowledged.
Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.03(a)).
Applicant further elected without traverse the following species:
The genus of method steps for producing particulated tissue with an isotonic solution of claim 1.
In light of the Applicant’s elected invention and species, claims 16-21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
DETAILED ACTION
The amended claims filed on July 23, 2026, have been acknowledged. Claims 2 and 6 were cancelled. Claims 1 and 4-5 were amended. In light of the Applicant’s elected group and species, claims 16-21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 1, 3-5, and 7-15 are pending and examined on the merits.
Priority
The applicant claims domestic priority from U.S. provisional application No. 62/838,245, filed on April 24, 2019. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Claims 1, 3-5, and 7-15 receive domestic benefit from U.S. provisional application No. 62/838,245, filed on April 24, 2019.
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, 3-5, 7-9, and 12-15 are rejected under 35 U.S.C. 103 as being unpatentable over United States Patent Application No. 20160287752 (Britt), United States Patent Application No. 20150086573 (Brahm), Myrissa et al. (Acta Biomaterialia 48: 521–529. 2017), United States Patent Application No. 20180044629 (Qin), and Pal et al. (J Tissue Eng Regen Med 2: 436–444. 2008), as evidenced by LabMakelaar (Retsch ZM200 Ultracentrifugal Mill). This is a new rejection made in response to Applicant’s amendments to claim 1 further defining the structure of the rotor mill. Applicant’s traversal has been fully considered but is moot in response to the new rejection of record.
Regarding claims 1 and 3, Britt teaches a method of producing a particulated (i.e. morselized) tissue comprising viable mesenchymal stem cells comprising:
obtaining a soft tissue sample (placenta samples were collected during delivery by Cesarean section or vaginal delivery. The combined fetal membranes (amniotic membrane (AM) and chorionic membrane (CM)) are dissected from the maternal placental plate (decidua). Using sterile forceps, the AM is peeled from the CM, which separates at the AM basement membrane/CM stromal interface);
mincing the tissue sample to produce a minced tissue (under sterile conditions, fresh AM is cut into approximately 1 cm-wide strips using tissue Scissors);
morselizing the minced tissue (The cut strips of AM are then morcellized using a variable speed tissue homogenizer at between 500 and 1000 rpm for a brief, limited time. Morcellization is stopped when the AM is grossly shredded into tiny pieces by visual inspection, typically after no longer than five to fifteen seconds, depending upon the amount of specimen being processed. The individual pieces are visible and fall within in an approximate range of 0.1 mm to 1.0 mm in size)
collecting the particulated tissue comprising viable cells (The morselized AM is then collected for further processing or mixing with amniotic fluid. The AM is morcellized but not ground. A morcellized amnion may comprise amniocytes which are disrupted along with non-disrupted, viable amniocytes. Preparations with disrupted amniocytes have a higher concentration of growth factors, other functional protein and peptide molecules, and other biologically active molecules which are released into the preparation from the disrupted cells. Non-disrupted viable amniocytes comprise SCs (identified as mesenchymal stem cells in paragraph 0024) which become engrafted into host tissue and participate in tissue regeneration and lend other highly beneficial, therapeutic effects to the tissue graft) (paragraphs 0024 and 0043-0056).
Britt does not teach adding the minced tissue to a processing chamber comprising a collection pan, a sieve, and a toothed rotor.
However, Brahm teaches a method of morselizing placental tissue and that tissue morselization may occur by any art-recognized method of tissue disruption, including milling and homogenizing (paragraph 0062).
Myrissa teaches that they pulverized liver tissue samples (a soft tissue that is comparable to that of placental amniotic membrane tissue) in an ultra-centrifugal mill (ZM 200, Retsch GmbH, Haan, Germany), equipped with a stainless steel 8 teeth rotor and 1 mm ring sieve to ensure homogeneity (page 523, column 1, paragraphs 4-6).
As can be seen in LabMakelaar (Retsch ZM200 Ultracentrifugal Mill), the Retsch mill used by Myrissa has a sieve, a toother rotor, and a collection pan (whole document). It is worth noting that the Retsch mill of LabMakelaar (and, by extension, Myrissa) looks nearly identical to the rotor mill used in Figure 1.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the homogenizer used in the method of processing placental tissue of Britt with a Retsch ultra-centrifugal rotor mill for morselization of the amniotic membrane tissue to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to substitute with a reasonable expectation of success because Brahm teaches that milling and homogenization are known to be equivalent methods for morselizing placental tissue and Myrissa teaches that the Retsch ZM200 Ultracentrifugal Mill can be used to pulverize and homogenize a comparable soft tissue (liver). Therefore, it would have been well understood the Retsch ZM200 Ultracentrifugal Mill could be used to morselize the placental tissue of Britt as milling and homogenizing were reasonable substitutes for morselizing placental tissue. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
The simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” “Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06.
The combined teachings of Britt, Brahm, and Myrissa do not teach wherein a frozen isotonic solution is added to the rotor mill before adding the unfrozen tissue.
However, Qin teaches a method of producing particulated tissue comprising:
obtaining a soft tissue sample (Human placenta was obtained from Caesarean section with donor consent);
mincing the tissue sample to produce a minced tissue (the placental membrane was cut into small (about 1-2 cm by 1-2 cm or 0.5 cm x 0.5 cm) pieces (e.g. crude fragments));
loading an isotonic solution into a processing chamber;
adding the minced tissue to the isotonic solution in the processing chamber (About 12 grams of placental membrane and three pieces of ice cubes were mechanically dispersed together for 2 minutes, and three more pieces of ice cubes were added into the mixture and dispersed for another minute)
dissociating the minced tissue in the processing chamber into the particulated tissue (tissues were mechanically dissociated using a homogenizer); and
collecting the particulated tissue (Then the dispersed soft tissue was transferred onto a sterile sieve and transferred into molds).
Qin teaches that the soft tissue may be dispersed mechanically by chopping, skiving, milling, grinding, slicing and/or beating the soft tissue. The temperature of the soft tissue may rise above ambient temperature due to the dispersing process. The temperature of soft tissue may be controlled by adding cold solution or ice (e. g., made from water or isotonic solution) to the soft tissue prior to, or during, the dispersing process (Examples 7 and 14 and paragraphs 0038-0041).
Pal teaches that for clinical applications, MSCs need to be stored in optimal conditions so that they may be transported and made available as an off-the-shelf product for transplantation. It is believed that these cells require a very strictly controlled environment in order to remain viable and healthy from the time of cell processing and while being transplanted into patients. Many surgical processes for stem cell transplantation take a long time, e.g. burr hole surgeries for Parkinson’s disease or intra-coronary injections for myocardial infarction. It may likely happen that the viability of the MSCs may decrease while waiting for transplantation.
Freshly harvested and cultured or frozen–thawed bone marrow-derived MSCs were prepared for cell transplantation. Both freshly cultured or frozen–thawed MSCs were washed and resuspended in parenteral solutions, either 0.9% saline, Dulbecco’s phosphate-buffered saline (DPBS), plasmalyte A or 5%dextrose and held for 2, 4, 6 and 8 h at 4◦C, 37◦C and RT (22◦C). The viability of the cells, differentiation capability and expression of cell surface markers were analysed. MSCs harvested from fresh cultures, resuspended in the parenteral solutions and maintained at 4◦C for 6 h showed more than 90% viability and exhibited better maintenance of viability compared to 37◦C and RT (22◦C). In contrast, frozen–thawed cells can be held for a maximum of 2 h after thawing before losing their viability significantly below permissible limits for transplantation (abstract and page 437, column 1, paragraph 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of processing placental tissue of the combined teachings of Britt, Brahm, and Myrissa by introducing an isotonic solution as ice during the morselization step to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because Qin teaches that the dispersing step (i.e. morselization) can cause temperature increases and using an isotonic solution in ice form can help control the temperature by limiting the temperature increase caused by homogenization. Furthermore, Pal teaches that MSC viability is negatively impacted by increasing temperature as MSC viability was reduced at 37◦C and RT (22◦C) compared to 4◦C. As such, it would have been obvious to add the ice to maintain the temperature of the tissue and viable mesenchymal stem cells that are desired by Britt around 4◦C compared to higher temperatures as this was shown to be beneficial for maintaining the viability of the MSCs. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding the steps of placing the ice in the processing chamber, then adding the minced tissue (steps c-d of claim 1), the combined teachings of Britt, Brahm, Myrissa, Qin, and Pal are silent as to the order of introducing the iced isotonic solution and the minced tissue to the processing chamber.
It would have been obvious to the ordinary artisan that one would want to add the ice to the chamber prior to adding the tissue to the processing chamber as the results from Pal show that MSCs viability is sensitive to temperature. By placing the ice in the chamber first, it would allow the chamber to reach a stable low temperature below room temperature prior to adding the placental tissue to ensure that the chamber is already cold and that the MSCs do not lose viability by being maintained at room temperature for an extended period of time. As such, it would have been obvious that the ice could be added to the processing chamber prior to adding the minced tissue. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Furthermore, even if there wasn’t a scientific rationale for placing the ice in the processing chamber first, it would have been obvious to one of ordinary skill in the art to choose from a finite number of identified, predictable options because “a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipate success, it is likely that product not of innovation but of ordinary skill and common sense.” "A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at ___, 82 USPQ2d at 1396.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) (Prior art reference disclosing a process of making a laminated sheet wherein a base sheet is first coated with a metallic film and thereafter impregnated with a thermosetting material was held to render prima facie obvious claims directed to a process of making a laminated sheet by reversing the order of the prior art process steps.). See also In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) (selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.).
Regarding claim 4, as stated supra, Britt teaches that under sterile conditions, fresh AM is cut into approximately 1 cm-wide strips using tissue Scissors (paragraph 0054).
Regarding claim 5, Britt teaches that under sterile conditions, fresh AM is cut into approximately 1 cm-wide strips using tissue Scissors (paragraph 0054).
Britt does not teach wherein the minced tissue is about 0.2 cm2 to about 0.5 cm2.
However, as stated supra, Qin teaches that minced (crudely fragmented) tissue can be cut into 0.5 x 0.5 cm pieces (equates to 0.25 cm2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that the minced tissue sample pieces of Britt could be about 0.25 cm2, as identified by Qin, instead of 1 cm2 strips as used by Britt to arrive at the instantly claimed invention. One of ordinary skill in the art would reasonably understand that an isolated placental tissue could be cut into 0.25 cm2 pieces as Qin specifically teaches that minced (crudely fragmented) tissue can be cut into 0.5 x 0.5 cm pieces (equates to 0.25 cm2) before milling the tissue. As such, it would have been obvious to one of ordinary skill in the art that placental tissue could be cut into 0.25 cm2 pieces instead of 1 cm2 as both were known sizes used within the art for generating placental particulate tissue. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 7, Qin teaches that the ice can be 1 cm3 (equates to 1 cm2) (paragraph 0044).
Regarding claim 8, Qin, as stated supra, teaches that temperature of soft tissue may be controlled by adding ice (e.g., an isotonic solution) to the soft tissue prior to the dispersing process (paragraph 0041)
Regarding claim 9, Myrissa, as stated supra, teaches that they pulverized liver tissue samples (a soft tissue that is comparable to that of placental amniotic membrane tissue) in an ultra-centrifugal mill (ZM 200, Retsch GmbH, Haan, Germany), equipped with a stainless steel 8 teeth rotor and 1 mm ring sieve to ensure homogeneity (page 523, column 1, paragraphs 4-6).
Myrissa does not teach using a sieve wherein the pore size is about 500 μm.
However, Britt teaches that after morselization, the individual pieces are visible and fall within in an approximate range of 0.1 mm to 1.0 mm in size (paragraph 0054).
It would have been obvious that one could use a sieve wherein the pore size is about 500 μm as part of the combined method of Britt, Brahm, Myrissa, Qin, and Pal as this would allow for separation of smaller morselized pieces closer to the 0.1 mm range from the larger pieces around the 1.0 mm so that the larger pieces can undergo additional milling to reduce the overall size and achieve a more homogenous size and limit the variability between samples.
Regarding claims 12-13, Britt, as stated supra, teaches that morcellization is stopped when the AM is grossly shredded into tiny pieces by visual inspection, typically after no longer than five to fifteen seconds, depending upon the amount of specimen being processed. Furthermore, in the case where the claimed ranges "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). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I). Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 14, the combined teachings of Britt, Brahm, Myrissa, Qin, and Pal do not teach wherein the processing chamber is purged with the isotonic solution to collect residual particulated tissue.
However, the concept of quantitative transfer is well understood in the field and it would have been obvious to purge the processing chamber with the isotonic solution as a liquid to collect any residual tissue to ensure no sample is lost when transferring to a new container, such as one for mixing the morselized amniotic membrane tissue and amniotic fluid (AF). Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 15, the combined teachings of Britt, Brahm, Myrissa, Qin, and Pal do not teach wherein the processing chamber is purged with an additional isotonic solution to collect residual particulated tissue.
However, Britt, as stated supra, teaches that the morcellized amniotic membrane tissue with the amniotic fluid (paragraph 0056). Furthermore, the concept of quantitative transfer is well understood in the field and it would have been obvious to purge the processing chamber with multiple purge steps using isotonic solutions as a liquid to collect any residual tissue to ensure no sample is lost when transferring to a new container, such as one for mixing the morselized amniotic membrane tissue and amniotic fluid. As the amniotic fluid is part of the final mixed solution, it would have been well understood that the final step of quantitative transfer could use the amniotic fluid solution for purging and collecting the morselized tissue. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Claims 1 and 10-13 are rejected under 35 U.S.C. 103 as being unpatentable over United States Patent Application No. 20160287752 (Britt), United States Patent Application No. 20150086573 (Brahm), Myrissa et al. (Acta Biomaterialia 48: 521–529. 2017), United States Patent Application No. 20180044629 (Qin), and Pal et al. (J Tissue Eng Regen Med 2: 436–444. 2008), as applied to claim 1 above and further in view of United States Patent Application No. 20220047774 (Imming; has an effective filing date of February 21, 2019). This is a new rejection made in response to Applicant’s amendments to claim 1 further defining the structure of the rotor mill. Applicant’s traversal has been fully considered but is moot in response to the new rejection of record.
The combined teachings of Britt, Brahm, Myrissa, Qin, and Pal are discussed above.
The combined teachings of Britt, Brahm, Myrissa, Qin, and Pal do not teach wherein the milling occurs at about 6000 rpm.
However, Imming teaches that sliver-sized and-shaped muscle tissue (a soft tissue comparable to placental tissue) may be produced using a Retsch Mill for milling starting muscle tissue at about 5000 rpm for about 10 seconds. Regardless of whether the muscle tissue is in the form of particulates are slivers, the range for the speed of milling may be from about 1,000 rpm to about 10,000 rpm. Furthermore, other types of mills are also suitable to perform one or more size and/or shape modification steps to produce muscle tissue in the form of smaller slivers or particulates (paragraph 0090).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of processing placental tissue of the combined teachings of Shalini and Qin by using about 6000 rpm to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because Imming successfully reduces to practice that ~6000 rpm is a viable speed for particulating a comparable tissue (muscle in Imming and amnion in Britt) using a Retsch mill. Therefore, it would have been obvious that ~6000 rpm could be used for milling the placental tissue in the Retsch ZM200 Ultracentrifugal Mill.
Furthermore, in the case where the claimed ranges "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). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I). Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/KEENAN A BATES/Examiner, Art Unit 1631
