DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Action Is Final
Applicants' response to the Non-Final Office Action mailed on 19 May 2025, has been entered and the Remarks therein, filed on 17 September 2025, are fully considered here.
It is noted that references have been added for evidentiary purposes in the Response to Arguments section.
Status of Claims
Claims 66-80 and 82 are pending.
Claims 66-80 and 82 are rejected.
Priority
Applicant has claimed the benefit of the filing date of the prior application, and designates the instant application as a "CON" of 16/164,274.
However, as noted in the last office action the instantly-claimed subject matter is not fully supported under 35 USC §112 by provisional application 61/442,346, filed 14 February 2011 (MPEP 2152.01 (C)). The subject matter of claims 73, 74, 76-79 and 82 are supported by either provisional application 61/543,995 or PCT/US2012/024798. Therefore, claims 76, 78 and 79 have the effective filing date of 06 October 2011. Claims 73, 74, 77 and 82 have the effective filing date of 13 February 2012. Claims 66-72, 75 and 80 have the effective filing date of 14 February 2011.
Claim Interpretations
(1) Claim 66 recites: “A method of preparing human micronized placental tissue particles,…; and v) micronizing said amnion and said chorion; thereby forming micronized human placental tissue particles.”
The specification does not describe, explain or define what is meant by the terms ‘micronized’ or ‘micronizing’. The specification does recite: “…, the micronized composition has particles that are less than 500 μm, less than 400 μm, less than 300 μm, or from 25 μm to 300 μm, from 25 μm to 200 μm, or from 25 μm to 150 μm. In certain aspects, particles having a larger diameter (e.g. 150 μm to 350 μm) are desirable” (originally-filed specification, pg. 12, para. [0039]); and “…, the micronized particles (e.g., micronized amnion/chorion tissue graft) having a particle size from 150 μm to 350 μm can be effective in wound healing…” (pg. 31, para. [0087]).
That is, the specification does give examples of what the sizes are of the particles in the micronized composition, and these sizes fall within a ‘micron-size’ range (or smaller, such as nanometer).
For the purpose of examination, prior art which shows placental tissue particles which are described as being ‘micronized’ or prior art which shows placental tissue particles that fall within a ‘micron-size’ range (or smaller) will be considered to address the limitation.
(2) Claim 71 recites: “…, further comprising adding a bioactive agent to the amnion and chorion.”
The specification recites: “…, reference to ‘a bioactive agent’ includes mixtures of two or more such agents, and the like (spec., pg. 2, para. [0009]); and “Examples of bioactive agents include,…, naturally occurring growth factors sourced from platelet concentrates,…; or antibiotics” (pg. 13, para. [0044]).
That is, the specification describes examples of bioactive agents, but does not provide a definition of the term. An American dictionary definition of the term ‘bioactive agent’ is: substances that can influence an organism, tissue or cell.
For the purpose of examination, prior art will be applied according to broadest reasonable interpretation of the term, e.g., according to the dictionary definition. (It is noted that ‘antibiotics’ is cited as an example of a bioactive agent in the specification.)
(3) Claim 74 recites: “…, wherein the amnion in the micronized placental tissue particles have had their epithelial layer substantially removed.”
The specification recites: “The term ‘substantially removed’ with respect to the amount of epithelium removed is defined herein as removing greater than 90%, greater than 95%, or greater than 99% of the epithelial cells from the amnion” (spec., pg. 7, para. [0028]).
Therefore, prior art which shows that the epithelial layer is substantially or completely removed will be considered to be address the limitation. Any descriptions in the prior art which show an epithelial layer removal percentage of greater than 90% will be considered to address the limitation.
(4) Claim 75 recites: “…, further comprising cross-linking the amnion and the chorion.”
Examples of compounds or processes which can be used to cross-link the various tissue layers are cited in the specification (e.g., spec., pg. 14, para. [0045] thru pg. 15, para. [0047]).
Therefore, prior art which shows any of the compounds or processes exampled in the specification will be considered to address the limitation ‘cross-linked’ whether or not the compound or process is described as such in said prior art. In addition, prior art which shows a compound which is described as crosslinking amnion and chorion will also be considered to address the limitation. It is noted that ‘sugar’ and its various forms are cited in the specification as examples of a crosslinking agent (spec., pg. 15, para. [0047]). It is also noted that glutaraldehyde, oxidized dextran and EDC are also cited as examples of crosslinking agents (spec., pg. 14, para [0046]).
(5) Claim 76 recites: “…, wherein the amnion and chorion are dehydrated by chemical dehydration.”
The specification recites: “…, the tissue (i.e., individual membrane or graft) is dehydrated by chemical dehydration followed by freeze-drying…, the chemical dehydration step is performed by contacting the amnion, chorion, and/or intermediate layer with a polar organic solvent…Examples of polar organic solvents useful herein include, but are not limited to, alcohols, ketones, ethers, aldehydes, or any combination thereof. Specific, non-limiting examples include DMSO, acetone, tetrahydrofuran, ethanol, isopropanol, or any combination thereof” (spec., pg. 10, para. [0034]).
Therefore, prior art which shows any of the compounds or processes exampled in the specification will be considered to address the limitation ‘chemical dehydration’ whether or not the compound or process is described as such in said prior art. Prior art which teaches that the amnion and chorion are dehydrated by chemical dehydration will also be considered to be applicable prior art (regardless of the specific process utilized).
Claim Rejections - 35 U.S.C. § 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 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 pre-AIA 35 U.S.C. §103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. §103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. §103(c) and potential pre-AIA 35 U.S.C. §102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. §103(a).
Claims 66-80 are rejected under pre-AIA 35 U.S.C. §103(a) as being unpatentable over Tseng et al. (Pub. No. US 2007/0071828 A1) in view of Liu et al. (Pub. No. US 2007/0021762 A1), and Daniel et al. (Pub. No. WO 2009/033160 A1).
[This rejection cited in the Non-Final Office Action mailed 19 May 2025.]
Tseng et al. addresses some of the limitations of claim 66.
Regarding claim 66, pertaining to a method of preparing human placental tissue particles,
Tseng et al. shows purified compositions and amniotic membrane preparations (that is, compositions that are prepared from amniotic membrane materials, including the amniotic membrane, amniotic stroma and amniotic jelly) (pg. 1, para. [0005]). Pharmaceutical formulations are provided that include particles of the compositions as described (pg. 15, para. [0165]). The composition comprises at least one component prepared from human amniotic material selected from, minimally, a human amniotic membrane (pg. 1, para. [0007]).
Further regarding claim 66, pertaining to i) providing a human amniotic sac collected during a Cesarean section birth,
Tseng et al. teaches that the amniotic membrane (AM) is an avascular membranous sac that is filled with amniotic fluid (pg. 1, para. [0004]). Tseng et al. shows that the preparation of human AM involves the collection of human placenta at an elective cesarean delivery (pg. 8, para. [0098]).
Further regarding claim 66, pertaining to the amniotic sac comprising an amnion and a chorion,
Tseng et al. shows purified compositions in which at least one component of the purified composition is obtained from human placenta and chorion (pg. 1, para. [0005]).
Further regarding claim 66, pertaining to ii) removing clotted blood from said amnion and said chorion,
Tseng et al. shows that human placenta as well as chorion obtained from Baptist Hospital was rinsed to remove blood (pg. 9, para. [0106]).
Further regarding claim 66, pertaining to iii) chemically decontaminating said amnion and said chorion using an antibiotic solution, thereby forming amnion and chorion comprising an antibiotic,
Tseng et al. shows that AM preparations can be in a liquid, suspension, or lyophilized powder (e.g., ground or pulverized), or other forms. Antimicrobial agents such as antibiotics or antifungal agents may be added (pg. 7, para. [0089]).
That is, if the AM preparations are in a liquid, addition of the antibiotics will render an antibiotic solution.
Further regarding claim 66, pertaining to v) dehydrating said amnion and said chorion,
Tseng et al. shows that an exemplary method of removing the water is by the use of lyophilization using a commercially available lyophilizer or freeze-dryer (pg. 7, para. [0090]).
Further regarding claim 66, pertaining to vi) forming human placental tissue particles,
Tseng et al. shows that pulverizing the tissue while frozen, rather than grinding the tissue prior to freezing, is one optional method for preparing the tissue. Alternatively, fresh, partially thawed, or thawed tissue can be used in the grinding step. The tissue is ground into fine particles using a BioPulverizer or other suitable devices (pg. 7, para. [0083]).
Tseng et al. does not specifically show: 1) that the human placental tissue particles are micronized; and 2) iv) removing said antibiotic from said amnion and chorion formed in step iii).
Liu et al. addresses some of the limitations of claim 66.
Liu et al. shows a plug comprising a cap and a shaft, the shaft having a surface, a length and two ends, said shaft extending from the cap, wherein said plug is made of a biodegradable composition. In another more specific embodiment, said composition is derived from amniotic membrane (pg. 1, para. [0010] [nexus to Tseng et al.- composition comprising amniotic membrane]). The described invention also provides a method for preparing an ocular plug made from a placental membrane, preferably a chorionic and/or amniotic membrane (pg. 1, para. [0002] [nexus to Tseng et al.- composition comprising amniotic membrane and chorion]).
Regarding claim 66, pertaining to a method of preparing human micronized placental tissue particles; vi) micronizing said dehydrated amnion and chorion, thereby forming micronized human placental tissue particles,
[See Claim Interpretations section- (1) above.]
Liu et al. shows that the described invention further provides a method of making an ocular plug, comprising: (a) micronizing a dried amniotic membrane to produce micronized amniotic membrane (pg. 2, para. [0013]).
Daniel et al. addresses some of the limitations of claim 66.
Daniel et al. shows tissue grafts and methods of making and using thereof. The tissue grafts are multilayered systems composed of one or more membranes laminated to a base amnion. The preparation steps include obtaining a placenta from a subject, wherein the placenta comprises an amniotic membrane layer and a chorion tissue layer (pg. 4, lines 10-17 [nexus to Tseng et al.- method incorporating providing an amniotic sac/membrane comprising an amnion and a chorion]). Human placentas that meet selection criteria are preferably bagged in a saline solution in a sterile shipment bag and stored in a container of wet ice for shipment (pg. 6, lines 1-2 [nexus to Tseng et al.- human placental tissue]).
Regarding claim 66, pertaining to iv) removing said antibiotic from said amnion and chorion formed in step iii),
Daniel et al. shows that the amnion is placed into a sterile Nalgene jar for the next step for additional cleaning with regard to chemical decontamination. If the chorion is to be recovered and processed further, it too is placed in its own sterile Nalgene jar for additional cleaning (pg. 9, lines 1-4). The tissue is placed into an empty Nalgene jar. The empty Nalgene jar with the tissue is then aseptically filled with a pre-mixed antibiotic solution. This jar or container containing the tissue and antibiotics is then sealed or closed and placed on a rocker platform and agitated. Such rocking or agitation of the tissue within the antibiotic solution further cleans the tissue of contaminants and bacteria. Using sterile forceps, the tissue is gently removed from the jar or container and placed in a sterile basin containing sterile water or normal saline (0.9% saline solution). The tissue may be slightly agitated to facilitate removal of the antibiotic solution and any other contaminants from the tissue. After at least 10 to 15 minutes, the tissue is ready to be dehydrated and processed further (pg. 9, lines 11-29 thru pg. 10, lines 1-3 [nexus to Tseng et al.- decontaminating the amniotic membrane (AM) preparations with an antibiotic]).
Accordingly, it would have been obvious to one of ordinary skill in the art at the time that the claimed invention was made, to have modified the method of preparing human placental tissue particles comprising an amnion and a chorion, as shown by Tseng et al., by micronizing the dehydrated human placental tissue [Claim 66, step vi)], as shown by Liu et al., with a reasonable expectation of success, because Liu et al. shows a method of preparing human micronized placental tissue particles from amniotic membrane, which is the method of preparing human placental tissue particles, as shown by Tseng et al. (MPEP 2143 (I)(G)).
Even in the absence of Liu et al., it would have been obvious to have micronized the human placental tissue shown by Tseng et al., because Tseng et al. shows that the amniotic and chorionic tissue was ground into fine particles using a BioPulverizer. Therefore, it would have been obvious to one of ordinary skill in the art to have used routine optimization to have ground the amniotic membrane shown by Tseng et al. into particles of a specific, desired size, such as micron-sized particles (or smaller), depending on the potential therapeutic application of said particles (MPEP 2144.05 (II) and MPEP 2144 (I)).
One of ordinary skill in the art would have been motivated to have made that modification, because one of ordinary skill in the art of repairing damaged tissue would recognize that human placental tissue particles which are ‘micron-sized’ would be able to penetrate damaged tissue more effectively (e.g., rather than millimeter-sized particles); for example, for use in any type of wound healing application.
It would have been further obvious to have removed said antibiotic from said amnion and chorion formed in step iii) [Claim 66, step iv)], as shown by Daniel et al., with a reasonable expectation of success, because Daniel et al. shows a method for chemically decontaminating amnion and chorion tissue by adding antibiotics (as a solution), which is the method for decontaminating amnion and chorion shown by Tseng et al., which, in turn, shows amnion and chorion membrane preparations which can contain an antibiotic in solution (MPEP 2143 (I)(G)).
One of ordinary skill in the art would have been motivated to have made that modification, because one of ordinary skill in the art of administering amniotic membrane (AM) preparations (as micronized human placental tissue particles or as layers of placental tissue) would prefer to remove the antibiotic solution in order to avoid any potentially detrimental allergic reactions that the recipient of said AM preparations might have to said antibiotics. Daniel et al. teaches that the premixed antibiotic solution is comprised of a cocktail of antibiotics, such as Streptomycin Sulfate and Gentamicin Sulfate. Other antibiotics, such as Polymixin B Sulfate and Bacitracin are also suitable (Daniel et al., pg. 9, lines 15-18). Therefore, the practitioner who inserts or injects AM preparations into a subject would want to avoid administering said preparations which contain sulfate derivatized antibiotics or bacitracin which might cause allergic reactions in said subject by removing the antibiotic after it has been used to “sterilize” or decontaminate the AM preparation(s).
In addition, one of ordinary skill in the art of antibiotic administration would prefer to remove antibiotics after their use in decontaminating a tissue preparation to be used for therapeutic purposes in order to reduce the risk of encouraging the growth of antibiotic-resistant bacteria.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill at the time the invention was made.
Tseng et al. further addresses the limitations of claims 69, 70, 71, 72, 73, 75, 76, 77, 79 and 80.
Regarding claim 69, and
regarding claim 70, pertaining to biocellulose polymers or copolymers,
Tseng et al. shows that pharmaceutical solid dosage forms can include one or more pharmaceutically acceptable additives such as, minimally, a compatible carrier, binder, filling agent or one or more combination thereof (pg. 14, para. [0156]). ‘Binders’ impart cohesive qualities and include, minimally, cellulose derivatives such as carboxymethylcellulose, methylcellulose (e.g., Methocel®) hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®), ethylcellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g., Avicel®) (pg. 2, para. [0011]).
Regarding claim 71, pertaining to bioactive agent,
[See Claim Interpretations section - (2) above.]
Tseng et al. shows that AM (amniotic membrane) preparations can be in a liquid, suspension, or lyophilized powder (e.g., ground or pulverized), or other forms. Antimicrobial agents such as antibiotics or antifungal agents may be added (pg. 7, para. [0089]).
Regarding claim 72, pertaining to a fibrin glue,
Tseng et al. shows that water-soluble or lyophilized AM preparations can be mixed with collagen, fibrin or with HA (hyaluronic acid) (pg. 8, para. [0094]).
Regarding claim 73, the amniotic membrane (AM) is an avascular membranous sac that is filled with amniotic fluid. This membrane is the innermost membrane surrounding a fetus in the amniotic cavity. This tissue consists of an epithelial layer and a subadjacent avascular stromal layer (pg. 1, para. [0004]).
Regarding claim 75, pertaining to cross-linking the amnion and chorion,
[See Claim Interpretations section- (4) above.]
Tseng et al. shows that ‘binders’ impart cohesive qualities and include, minimally, a sugar, such as sucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®), and lactose (pg. 2, para. [0011]).
Regarding claim 76, pertaining to chemical dehydration,
[See Claim Interpretations section- (5) above.]
Tseng et al. shows that solvents are generally employed in the preparation of suitable compositions. Such solvents can either be aqueous or organic based (pg. 11, para. [0121]).
Regarding claim 77, the tissue can be frozen prior to the grinding process. The freezing step can occur by any suitable cooling process. For example, the tissue can be flash-frozen using liquid nitrogen (pg. 7, para. [0082]). AM preparations can be in a liquid, suspension, or lyophilized powder (e.g., ground or pulverized), or other forms (pg. 7, para. [0089]).
Regarding claim 79, the tissue is ground into fine particles using a BioPulverizer or other suitable devices (pg. 7, para. [0083]).
Regarding claim 80, pulverizing the tissue while frozen, rather than grinding the tissue prior to freezing, is one optional method for preparing the tissue. The tissue (fresh, frozen, or thawed) can then be sliced into pieces of a desired size with a suitable device, such as a scalpel, then ground to fine particles using a BioPulverizer (pg. 7, para. [0083]).
Liu et al. further addresses the limitations of claims 67, 68 and 78.
Regarding claims 67 and 68, Liu et al. shows that the described invention provides a method of making an ocular plug, comprising: (a) micronizing a dried amniotic membrane to produce micronized amniotic membrane material. In a more specific embodiment, the median size of particles in said micronized amniotic membrane is 1 micron to 1 mm (pg. 2, para. [0013]).
Regarding claim 78, the amniotic membrane may be heat-vacuum dried to achieve a dehydrated amniotic membrane (pg. 18, para. [0223] thru pg. 19, cont. para. [0223]).
Daniel et al. further addresses the limitations of claim 74.
[See Claim Interpretations section- (3) above.]
Regarding claim 74, Daniel et al. shows that the epithelium layer of the base amnion of the multilayered membrane systems has been substantially removed (pg. 4, lines 10-14). After the epithelium layer is substantially removed from the amnion to expose the base membrane, acceptable tissue is then decontaminated and dehydrated (pg. 5, lines 5-9 [nexus to Tseng et al.- method steps of chemically decontaminating and dehydrating]).
Claim 82 is rejected under 35 U.S.C. §103(a) as being unpatentable over Tseng et al. in view of Liu et al., and Daniel et al., as applied to claims 66-80 above, and further in view of Schorgl et al. (International Patent Application Publication No. WO 2010/101780 A2) in view of Mizrahi et al. ((2011 Jan) Tissue Adhesives; In: Stud. Mechanobiol. Tissue Eng. Biomater. 8:39-56).
[This rejection cited in the Non-Final Office Action mailed 19 May 2025.]
Tseng et al. in view of Liu et al., and Daniel et al., as applied to claims 66-80 above, do not show: 1) the cross-linking is performed using oxidized dextran as a cross-linker [Claim 82].
Schorgl et al. and Mizrahi et al. provide information from which one of ordinary skill in the art of preparing micronized placental tissue particles would have understood that the amnion and chorion tissue, during the preparation method, as shown by Tseng et al. in view of Liu et al., and Daniel et al., could have been cross-linked with oxidized dextran as a cross-linker, by way of addressing the limitations of claim 82.
Schorgl et al. shows a biocompatible stent for placement in a vessel of a living subject (pg. 1, lines 27-28). In some embodiments, the biocompatible material comprises a plurality of layers of amnion tissue (pg. 2, lines 4-5). In some embodiments, the biocompatible material further comprises placental tissue (pg. 2, lines 24-26). The term 'placenta tissue' refers to any material comprising a composition from the amniotic sac, such as the amnion layer, the chorion layer, portions thereof or combinations thereof (pg. 8, lines 19-21 [nexus to Tseng et al., Liu et al., and Daniel et al.- a step of providing an amniotic sac comprising an amnion and a chorion]). The amnion tissue can be ground in a frozen or freeze-dried state, and then lyophilizing the material to produce a powder having particles (pg. 21, lines 14-17 [nexus to Tseng et al., Liu et al., and Daniel et al.- a method of preparing micronized placental tissue particles]).
Regarding claim 82, the most common chemical modification comprises crosslinking or partially crosslinking amnion tissue. Crosslinking of the tissue can provide mechanical stabilization of the material. Crosslinking agents such as glutaraldehyde, triglycidylamine, or EDC (1-Ethyl-3-[3-dimethylaminopropyl] carbodiimide Hydrochloride) can be used (pg. 19, lines 22-27).
Regarding claim 82, Mizrahi et al. teaches that tissue adhesives are substances that hold tissues together, and could be broadly applicable in medicine and surgery (pg. 39, Abstract). Tissue adhesives can be divided into three main chemical categories: cyano-acrylates, fibrin sealant, and other cross-linkable polymers (pg. 40, para. 2). BioGlue® is a surgical adhesive composed of purified bovine serum albumin (BSA) and glutaraldehyde (pg. 44, para. 1 [nexus to Schorgl et al.- glutaraldehyde as a crosslinking agent]). Figure 4 shows the structure of oxidized dextran (pg. 44, Fig. 4). One two- component system is made of aminated star-PEG (a star- shaped poly[ethylene glycol]) and high-molecular-weight dextran-aldehyde (Fig. 4) (pg. 44, para. 2). The aldehydes of the dextran are in excess of the amine groups in the star-PEG, and they are responsible for both cohesion and adhesion (pg. 45, lines 7-9). Another glue is composed of aldehyde-modified [i.e., oxidized] dextran and poly (L-lysine) (pg. 46, para. 2).
Accordingly, it would have been obvious to one of ordinary skill in the art at the time that the claimed invention was made, to have modified the method of preparing human micronized placental tissue particles comprising an amnion and a chorion, as shown by Tseng et al. in view of Liu et al., and Daniel et al., as applied to claims 66-80 above, by: 1) crosslinking the amnion and chorion using oxidized dextran as a crosslinker [Claim 82], with a reasonable expectation of success, because Schorgl et al. shows that placental tissue, which includes amnion and chorion, can be crosslinked (e.g., with glutaraldehyde), and Mizrahi et al. shows that a crosslinking polymer on a par with glutaraldehyde for crosslinking tissue together is oxidized dextran (MPEP 2143 (I)(G)).
Therefore, it would have been obvious to one of ordinary skill in the art of preparing human micronized placental tissue particles by including crosslinked amnion and chorion tissue in the preparation method, as shown by Schorgl et al., to have substituted the glutaraldehyde, shown by Schorgl et al., with the oxidized dextran, shown by Mizrahi et al., with the reasonably predictable expectation that the amnion and chorion would have become successfully crosslinked (MPEP 2143 (I)(B)(3)).
One of ordinary skill in the art would have been motivated to have made that modification, because Schorgl et al. teaches that crosslinking of the tissue can provide mechanical stabilization of the (biocompatible) material. Mizrahi et al. also teaches that water soluble polymers forming a three dimensional (3D) network have been used as tissue adhesives due to their safety, mechanical properties and ease of application. Cross-linking prevents early dissolution of the material, and maintains cohesive integrity (Mizrahi et al., pg. 43, para. 4).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill at the time the invention was made.
Response to Arguments
Applicant’s arguments, pp. 5-10, filed 17 September 2025, with respect to the prior art references cited in the 35 U.S.C. §103 rejections, have been fully considered, but they are not persuasive.
1. Applicant remarks (pg. 5, para. 4 thru pg. 6) that Applicant hereby incorporates by reference the remarks from pp. 5-7 of the Amendment dated March 13, 2025 filed in connection with the instant application relating to this ground of rejection. In brief, Applicant noted that i) there was no reason to reorder the steps of Tseng's methods in order to reach the present claims, and ii) there was no motivation to add a step of removing the antibiotic to Tseng' s methods involving adding an antibiotic, because doing so would defeat the purpose of adding the antibiotic in the first place ("to stabilize and/or preserve the compositions"). Applicant respectfully notes that there was no reason to add antibiotics to Tseng's compositions at a time that would facilitate their removal, because there was no evident need to remove them.
However, in response to Applicant, first, the term "antibiotics" only appears twice in the Tseng et al. reference. That is, there is no emphasis in Tseng et al. that antibiotics need to be added at all to the method of preparing the described placental tissue particles or that antibiotics need to be added to the final product. Tseng et al. teaches that antimicrobial agents such as antibiotics or antifungal agents may be added (pg. 7, para. [0089]). Therefore, it is clear that Tseng et al. does not require antibiotics to be present (i.e., they are optional)- and if they had been added, there is no teaching in Tseng et al. that requires that said antibiotics remain in any form of the composition (as a liquid, suspension or powder). Therefore, removal of said antibiotics would not defeat the purpose of adding antibiotics in the first place. (See Daniel et al. in the 103 rejection above in which antibiotics are added, then removed.) In addition, the comment in Tseng et al. quoted by Applicant (i.e., to stabilize and/or preserve the compositions) refers to "other substances" and not to antibiotics (Tseng et al., pg. 7, para. [0089]). The instantly-claimed method step of removing the antibiotic is addressed by the secondary reference of Daniel et al.
Further in response to Applicant, second, it is well known in the art that leaving antibiotics in pharmaceutical (tissue) preparations (if used previously to disinfect tissue) is questioned for several reasons (as is the general use of antibiotics): 1) the potential for the development of antibiotic resistance to said antibiotic; and 2) the potential for the development of allergic or anaphylactic reactions. That is, there are several reasons or motivations for decreasing the use of antibiotics (or removing antibiotics), including as ingredients in pharmacological preparations.
Kabins ((1972) JAMA 219(2): 206-212 (provided here)) teaches that with the increasing use of multiple therapeutic agents, it has become increasingly evident that the pharmacologic action of a drug may be quantitatively altered in patients receiving other drugs. Antibiotics may interact with unrelated nonantibiotic drugs, and the result may be the enhanced or decreased activity of the antibiotic or other drug (pg. 206, column 1, para. 1). Eastlund ((2006) Cell. Tissue Bank. 7:147-166 (provided here)) teaches that final sterility testing (of a tissue allograft) can be unreliable, especially when antibiotics remain on tissues (pg.147, Abstract). Lastly, Dua et al. ((2004) Surv. Ophthal. 49(1): 51-77 (provided here)) teaches that amniotic membrane has, in and of itself, antimicrobial properties (pg. 59, column 1, para. 2).
2. Applicant remarks (pg. 6, last para. thru pg. 7, para. 1) that paragraph [0150] reinforces Applicant's previous remarks - the formulations may comprise antibiotics which serve to "stabilize and/or preserve the compositions" by "prevention of growth of microorganisms." Removing the antibiotics would stop them from performing this function. Paragraph [0150] of Tseng does not explain how growth of microorganisms would be prevented by removing the antibiotics.
However, in response to Applicant, again, the phrase in Tseng et al. with regard to stabilizing and/or preserving the compositions is directed to "other substances" and not antibiotics (Tseng et al., pg. 7, para. [0089]). Similarly, Tseng et al. teaches that prevention of the growth of microorganisms can be ensured by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like (Tseng et al., pg. 13, para. [0150]). That is, Tseng et al. does not list classic drug antibiotics as being used to prevent the growth of microorganisms nor is the term 'antibiotics' used here. Although an 'antibacterial' agent is synonymous with the term antibiotic, one of ordinary skill in the art of using antibiotics as a pharmacological treatment would not include compounds such as parabens, chlorobutanol, phenol, and sorbic acid, in this treatment group, but rather would include drugs as noted by Daniel et al., i.e., streptomycin sulfate, gentamicin sulfate, polymyxin B sulfate and bacitracin (pg. 9, lines 15-18).
3. Applicant respectfully notes again that when Tseng describes adding antibiotics to a composition, these antibiotics are intended to be maintained within the composition, and delivered to the subject along with the rest of the composition.
However, in response to Applicant, the motivations for removing (or not using) antibiotics in a pharmaceutical (tissue) therapeutic are several and indicated above. Again, it is clear that Tseng et al. teaches that the inclusion of antibiotics in the described AM preparations is optional, and, therefore, the reference does not explain that antibiotics should be maintained in the composition so as to be delivered to the subject even if the antibiotics were included.
4. Applicant remarks (pg. 8, para. 2 thru pg. 9) that the rejection over Tseng, Liu, Daniel, Schorgl, and Mizrahi with regard to dependent claim 82 should be withdrawn. The deficiencies of Tseng in combination with Liu and Daniel are discussed hereinabove. Neither Schorgl nor Mizrahi cure these deficiencies; these references are cited for teachings relating to tissue adhesives and oxidized dextran. Applicant respectfully notes that Mizrahi does not teach that glutaraldehyde and oxidized dextran are equivalent in terms of crosslinking placental tissue. Mizrahi teaches that glutaraldehyde and oxidized dextran are both components of adhesives. Mizrahi teaches that"[c]ohesion strength is created by cross-linking between polymer chains, while adhesion forces are created by the reaction between the aldehyde and the amine groups in tissue." In other words, Mizrahi does not teach that the oxidized dextran is cross-linking to tissue, but that there is crosslinking occurring within the oxidized dextran; this is different from the cross-linking of tissue that Schorgl teaches.
However, in response to Applicant, Schorgl et al. teaches that crosslinking tissue agents include glutaraldehyde and Mizrahi et al. describes oxidized dextran as having aldehyde groups in excess of amine groups which are responsible for cohesion and adhesion (see 103 rejection above). The instant specification recites: "..., the crosslinking agent possesses groups that can react with amino groups present on the protein. Examples of such functional groups include,..., hydroxyl groups,..., and aldehyde groups" (originally-filed specification, pg. 14, para. [0046]). Therefore, one of ordinary skill in the art of crosslinking tissue would understand that the aldehyde groups on the oxidized dextran, as shown by Mizrahi et al., would react with tissue and facilitate crosslinking. This is essentially what Applicant is stating above. Therefore, Mizrahi et al. is teaching that oxidized dextran is crosslinking to tissue. Applicant's statement (that "this is different from the cross-linking that Schorgl teaches") appears to be opinion evidence, not supported by data or literature (MPEP 716.01 (c)(llI)).
Conclusion
No claims are allowed.
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/SMP/Examiner, Art Unit 1651
/Michelle F. Paguio Frising/Primary Examiner, Art Unit 1651