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 .
DETAILED ACTION
This Action is in response to the papers filed on September 16, 2024. Pursuant to the preliminary amendment filed on September 16, 2024, claims 1-13 are pending in the application of which claims 1-10 have been amended and claims 11-13 are newly filed. No claims have been cancelled. Therefore, claims 1-13 are currently under examination to which the following grounds of rejection are applicable.
Priority
The instant application claims foreign priority 35 U.S.C. 119(a)-(d) to Czech Patent Application CZECHIA PV 2022-116 filed on March 15, 2022 and the present application is a 35 U.S.C. 371 national stage filing of the International Application No. PCT/CZ2023/050013, filed on March 14, 2023.Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Thus, the earliest possible priority for the instant application is March 15, 2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on September 16, 2024 was filed. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification
Cross-Reference to Related Applications
The disclosure filed on September 16, 2024 is objected to because the cross-reference to related applications on the first page of the specification is not provided. The cross-reference should contain the priority applications listed above in addition to the respective patent numbers. Correction is required.
References in Specification
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892 or an official IDS, they have not been considered.
Claim Objections
Claims 8 and 10 are objected to because of the following informalities:
Claim 8 recites “a particle size of no more than 200 pm, with at least 95% of the particles having size of up to 5 pm,” yet it appears based on the Specification and Figure 1 that the intended units are not picometers, but rather micrometers (µm). This is further supported by the earlier claim sets which use micrometers with the same claimed numerical values.
Claim 8 is missing an “and” after “neurotrophic factors,”.
Claim 10 is missing an “and at the end of the recited list. Appropriate correction is required.
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.
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, 2, 4, 6, and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Tseng et al. (US 10,426,731; hereinafter ‘Tseng’) in view of Ghinelli (US 7,871,646 B2) as evidenced by Branson™ Sonifier by Emerson.
Tseng teaches a method for preparation of a biological therapeutic product based on perinatal tissue (“In some embodiments, the fetal support tissue is selected from an umbilical cord, placenta, placental amniotic membrane, umbilical amniotic membrane, chorion, amnion-chorion or any combination thereof.” (col 2, ln 8-11)) comprising the steps of:
a) cleaning of the starting perinatal tissue (“In some embodiments, the fetal support tissue is washed with buffer with agitation to remove excess blood and tissue.”(col 28, ln 1-2)) and/or shaping into sections whose dimensions do not exceed 50 mm in any direction (Example 9 describes cuttings of 2 x 2 cm (20 mm); and allowing the tissue to dry for at least 15 minutes after the cleaning (Example 2 and 3 discuss drying of placenta tissue after washing);
b) cryo-grinding of the perinatal tissue in resealable surgical steel capsules with surgical steel grinding balls (“5 ml of 2 x 2 cm AM were placed in the mortar. A 15 mm chrome steel grinding ball was dropped into the mortar and the lid was screwed on tight. The mortar was immersed horizontally in LN [liquid nitrogen] for 1 minute and was run on the mill for a 4 minute 30 Hz cycle” (Example 9));
c) homogenization of the ground perinatal tissue using an ultrasonic homogenizer (“In some embodiments, the lyophilized fetal support tissue is ground by use of a tissue grinder (e.g., a Potter-Elvehjem grinder or a Wheaton Overhead Stirrer). In some embodiments, the lyophilized fetal support tissue is ground by use of a sonicator. In some embodiments, the lyophilized fetal support tissue is ground by use of a bead beater. In some embodiments, the lyophilized fetal support tissue is ground by use of a freezer/mill (e.g., a SPEX SamplePrep Freezer/Mill).”(col 31, par 1));
d) transferring the ground and homogenized perinatal tissue into a primary packaging with constant stirring (“In some embodiments, the fetal support tissue powder product is aliquoted without prior freezing... In some embodiments, the aliquoted fetal support tissue powder product is packaged into a packet, a vial, a pre-filled syringe, or a bottle.” (col 2, ln 24-30));
e) lyophilization of the ground and homogenized perinatal tissue in the primary packaging (col 63; Table left side); and
f) sterilization of the lyophilized ground and homogenized perinatal tissue in the primary packaging by gamma radiation at a dose of 5 to 20 kGy (“In some embodiments, a fetal support tissue powder product disclosed herein is exposed to gamma radiation at about 10 to about 30 kGy for a period of time sufficient to sterilize the fetal support tissue powder product” (col 35, ln 61-64)) wherein the entire process is carried out without the presence of antibiotics and antimycotics as seen in the examples no including such compounds.
Tseng teaches the lyophilization as occurring after grinding & homogenization as seen in col 63, yet in the same section states it is preferable for lyophilization to occur prior which is further supported by the majority of examples. In particular, Example 9 describes how the best outcomes for amniotic tissue were observed were when lyophilization occurred prior to any grinding/homogenization as seen in run #7. However, run #4 shows homogenization when the griding was done at freezing temperatures which does coincide with the instant claim, yet the product could not be drawn / injected by an 18 gauge syringe for which the claims are not limited to. Therefore, Tseng does teach that lyophilization could occur after grinding/homogenization.
In further support of this order, Ghinelli teaches a method of preparing an amniotic membrane extract in which the method includes the steps of obtaining a healthy amniotic membrane, homogenizing the membrane to obtain a homogenate solution, freezing the homogenate solution, and then lyophilizing the frozen homogenate solution to powder form (col 2, ln 5-16; claim 1).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have switched the order of steps for the preparation of perinatal tissue as taught by Tseng wherein homogenization is followed by lyophilization because Ghinelli teaches such method is successful in obtaining a similar product, e.g. amniotic membrane extract wherein the final step is lyophilization and secondly, because Tseng teaches homogenization can be successful when not proceeded by lyophilization (Example 9). Secondly, it would be obvious to try in homogenizing the tissue prior to lyophilization based on choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success because all the steps in combination are taught in the prior art, and therefore would not require undue experimentation to test different combinations or orders of steps for optimization of obtaining the end product.
Regarding claim 2, Tseng teaches the fetal support tissue is washed which includes removing the blood and excess tissue, and contacting with the appropriate buffers, e.g. saline , PBS , PBS 1x , Ringer ' s solution , Hartmann' s solution , TRIS - buffered saline , HEPES - buffered saline , EBSS , HBSS , Tyrode ' s salt Solution , Grey ' s Balanced Salt Solution , DMEM , EMEM,GMEM , RPMI , or any combinations thereof (col 27-28). Tseng further states washing with agitation may reduce wash time, and further describes which tissues may be removed dependent on target fetal tissue, such as the removal of Wharton’s Jelly with surrounding veins and arteries.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have repeated the lavage and mechanical cleaning at least twice in order to further optimize the preparation of the therapeutic product as there would an expectation that further washing would lead a more uniform product devoid of contamination, and consequently an improved product. In support of this, Tseng alludes to washing can take a lengthy amount of time, and can be reduced by using agitation, and therefore it would be obvious to use multiple washings as it appears the preparation does require extensive washing.
Regarding claim 4, the rejection to claim 1 makes it clear that Tseng teaches the sonication of the perinatal tissue (col 31, par 1), and moreover Ghinelli additionally teaches the sonication using the Branson 250 Sonicator over the course of 3 steps of 3 minutes. As evidenced by the Branson sonicator product sheet, the employed model has a maximum output power of 250 watts (p 7, Table 1).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have optimized the sonication at select power thresholds and duration/cycles , e.g. pulses, to obtain an improved product, i.e. micronized tissue powder. Tseng teaches sonication is used for grinding the perinatal tissue, and furthermore Ghinelli teaches a particular model for grinding that allows for high power sonication, e.g. 250 watts. Therefore, it would be obvious to optimize the power and duration of sonication to obtain the claimed product based on it being well-known in the art of sonicators capable of meeting these claimed settings, and furthermore being used in a similar fashion on perinatal tissues to obtain a powdered homogenized form.
Regarding claim 6, Tseng teaches wherein the lyophilization step is performed at the lowest pressure value of 13 Pa and the lowest temperature of -60 °C, and the primary packaging is subsequently closed (“lyophilized at a temperature below about …−60° C”; “In some embodiments, the fetal support tissue is lyophilized at a pressure of 100 millitorr.[~13 Pa]” (col 29, ln 18-33)).
Regarding claim 11, dependent on claim 2, Tseng teaches the pharmaceutical composition is formulated for injection and the pharmaceutically-acceptable carrier may be water (col 9, ln 15-17; col 21, ln 60-66).
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Tseng et al. (US 10,426,731; hereinafter ‘Tseng’) in view of Ghinelli (US 7,871,646 B2) as applied to claim 1 above, and further in view of Spencer et al. (US 2015/0335686 A1; hereinafter ‘Spencer’).
The teachings of Tseng in view of Ghinelli are discussed supra. Tseng teaches the cry-grinding of the fetal support tissue is ground at a frequency of between about 10 Hz and about 25 Hz for any suitable time period, and states at lower frequencies a longer stretch of time as being necessary (col 31, ln19-30). Additionally, the container is pre-cooled prior to the start of grinding of the tissue (col 4, ln 30-34).
Regarding claim 3, Tseng and Ghinelli do not teach the cryo-grinding step is carried out in a cryogenic mill by pre-cooling with shaking at a frequency of at least 3 Hz and by grinding at a frequency of at least 20 Hz, in at least 4 grinding cycles, for a total duration of grinding cycles of at least 15 minutes, wherein during inter-cooling cycles the perinatal tissue is shaken at a frequency of at least 3 Hz.
Spencer teaches the cryo-grinding container is pre-chilled which are vials containing steel grinding balls then ground at 1,500 rpm [25 Hz] for 20 minutes, and then the tissue is inspected to ensure micronization. “If necessary, the tissue can be placed back into the Dewar for an additional 30-60 minutes, and moved to the grinder for an additional 20 minutes to ensure sufficient micronization.” (par 0131).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have optimized the cryo-grinding process by altering the number of grinding cycles, duration, and intensity to obtain an improved product, i.e. micronized tissue powder. Tseng teaches the claimed ranges for the grinding speed of at least 3 Hz, and furthermore describes the duration is an amount sufficient for homogenization, and Spencer further supports the claimed cycle length of at least 15 minutes by teaching grinding for 20 minutes, and occur more than once if necessary. Therefore, it would be obvious to optimize griding parameters that adequately homogenize the tissue sample based on it being shown in the art that grinding speed and duration can be optimized for homogenization of perinatal tissue to arrive at the claimed invention.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Tseng et al. (US 10,426,731; hereinafter ‘Tseng’) in view of Ghinelli (US 7,871,646 B2) as applied to claim 1 above, and further in view of Husnu et al. (US 9,139,316 B2; hereinafter ‘Husnu).
The teachings of Tseng in view of Ghinelli are discussed supra. Tseng teaches wherein the ground and homogenized perinatal tissue is filled into the primary packaging such as vials, packets, bottles and/or tubes (col 1, ln 64-67; Examples 5, 6).
Regarding claim 5, Tseng and Ghinelli do not teach wherein the ground and homogenized perinatal tissue is filled into the primary packaging using a peristaltic pump while stirring the ground and homogenized perinatal tissue.
Husnu teaches an improved vial filling that comprises a system of bulk vials in which a peristaltic pump moves then dispenses a pharmaceutical product to each container effectively and aseptically (abstract; col 2, ln 48-55; Fig. 1).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined a peristaltic pump to fill the primary packaging as taught by Tseng in view of Ghinelli based on Husnu teaching a system of using such pump for moving pharmaceutical compositions to vial. The motivation of using the peristaltic pump is provided by Husnu wherein the system allows for efficient controlled delivery with minimal risk of contamination based on occurring in an aseptic environment, and therefore it would be obvious use this system with the method taught by Tseng in view of Ghinelli to ascertain the therapeutic product is free of contamination and consequently a reduced risk in being used in treatments.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Tseng et al. (US 10,426,731; hereinafter ‘Tseng’) in view of Ghinelli (US 7,871,646 B2) and Husnu et al. (US 9,139,316 B2; hereinafter ‘Husnu’), as applied to claim 5 above, and further in view of Asp et al. (US 2,951,689 A; hereinafter ‘Asp’).
The teachings of Tseng in view of Ghinelli and Husnu are discussed supra. Tseng teaches wherein the ground and homogenized perinatal tissue is filled into the primary packaging such as vials, packets, bottles and/or tubes (col 1, ln 64-67; Examples 5, 6). Husnu teaches the vial filing system that employs a peristaltic pump wherein compositions are moved aseptically.
Tseng in view of Ghinelli and Husnu do not teach wherein the ground and homogenized perinatal tissue is stirred with a magnetic stirrer.
Asp teaches the first magnetic stir bar to be used with a fluid stirring apparatus, “In magnetic stirring apparatus, a vessel containing the liquid or other fluid material to be agitated is placed above a rotatably driven magnet, and a magnetized stirring bar is placed in the vessel. As the magnet is rotated, the stirring bar is intended to rotate about its own axis, and if the vessel is sufficiently large the bar will revolve thereabout while it rotates.” (col 1, ln 18-24).
It would have been obvious for one of ordinary skill in the art at the time of the effective filing date to have modified the method for preparation of a biological therapeutic product as taught by Tseng in view of Ghinelli and Husnu to incorporate a magnetic stir bar (as taught by Asp) because it would have been obvious to combine prior art elements according to known methods to yield predictable results. The incorporation of a magnetic stirrer to the bulk product vial (label 100 of Fig. 1) that is connected to a peristaltic pump (label 200 of Fig. 1) as the addition would have led to predictable results with a reasonable expectation of success of efficient aliquoting of uniform compositions, e.g. homogenized perinatal tissue to individual vials/containers (label 400 of Fig. 1).
Claims 7-10, and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Pavesio et al. (US 2023/0021803 A1; hereinafter ‘Pavesio’) in view of Rodella et al. (Wound Medicine 27.1 (2019): 100171.; hereinafter ‘Rodella’).
M.P.E.P. § 2113 reads, “Product-by-process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps.” “Even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 111 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985).
Claims 7-10 are considered product-by-process claims because the claims are directed to products obtained by the process of claim 1.
Regarding claims 7-10, Pavesio teaches a composition containing dehydrated placental tissue particulates (PTP) that are in the form of powder (abstract, par 0073-74) [regarding instant claim 7]. The PTP that have been cryo-milled are separated by size using the appropriate sieve wherein particulates ranging from 5 microns up to 300 microns can be separated accordingly (par 0051) [regarding instant claim 8]. Pavesio teaches the PTP as comprising quantifiable amounts of each of basic fibroblast growth factor (bFGF), interleukin-1 receptor antagonist (IL-1Ra), interleukin-1alpha (IL-1α), tissue inhibitor of metalloproteases (TIMP)-1, TIMP-2, TIMP-3, and fibronectin (par 0005-6; claim 7) [regarding instant claim 8]. The formulation may contain an auxiliary substance, “Pharmaceutical compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the PTP compositions into preparations which can be used pharmaceutically.”(par 0059); and furthermore include anti-inflammatories and corticosteroids [hormones] (par 0047) [regarding instant claims 8 and 9]. Lastly, Pavesio teaches the composition as being used for the treatment of inflammatory and degenerative diseases of musculoskeletal and connective tissues (par 0006) [regarding instant claim 10].
Pavesio does not teach, in respect to instant claim 8, at least 95% of the particles having size of up to 5 µm, that contains enzymes and neurotrophic factors.
In relation to the particle size percentage, Pavesio teaches particle size selection for which 5 µm is included, by using means of centrifugation or sedimentation or by passing through sieves (par 0051). Furthermore, “The process described herein provides a PTP composition having particles sized appropriately for delivery via syringe and provides processing procedures that do not adversely affect growth factors and cytokines of interest which are intrinsic to the placental tissue.” (par 0049). Therefore, it would be obvious to use size selection to obtain a uniform selection of particles that are 5 µm as these techniques are well-known in the art as described by Pavesio.
Rodella teaches powdered amniotic membrane for use in treating chronic diabetic ulcer, and confirmed the retention of healing factors, stating, “we quantified the presence of two neurotrophic (NGF and NT-3) and inflammatory (TGF-alpha, and IL1-ra) factors to confirm that proliferation and anti-inflammatory mediators present in the fresh membrane are maintained in the lyophilized form of the membrane.” (p 6, col 1; Tables 1 and 2). The effects were a strong angiogenesis and epithelium stimulation that was confirmed in the in vitro model of angiogenesis (conclusion).
It would have been obvious for one of ordinary skill in the art at the time of the invention to claimed the powdered perinatal tissues as comprising cytokines, embryonic growth factors, enzymes, extracellular matrix proteins, hormones, matrix metalloproteinases, neurotrophic factors, and protease inhibitors as part of the composition taught by Pavesio because Pavesio teaches select members of this grouping as being comprised and furthermore Rodella supports that the remaining members are also comprised in the powdered tissue form. Therefore these prior art teachings would have led one of ordinary skill to combine prior art reference teachings to arrive at the claimed invention.
In relation to the claimed particle size percentage, it would have been obvious for one of ordinary skill in the art at the time of the invention to select for a particular particle size based on the techniques of particle size selection being well-known in the art as taught by Pavesio, e.g. centrifugation or sedimentation or by passing through sieves, and furthermore Pavesio teaches particles as small 5 µm can be selected for therefore it would be obvious to use such techniques to arrive at the claimed invention.
Regarding claim 13, Pavesio teaches the pharmaceutical formulation is for the treatment of osteoarthritis by intra-articular administration (“Typically, the resuspended PTP compositions are administered directly to a target site (e.g., joints, surgical site, tendon). The administration of PTP formulations via intra-articular route and direct injection into a tendon,” (para 0065)).
Conclusion
Claims 1-13 are rejected. No claims are allowed.
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/MICHAEL ANGELO RIGA/Examiner, Art Unit 1634
/TERESA E KNIGHT/Primary Examiner, Art Unit 1634
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