DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . 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.
Priority
The instant application claims foreign priority to Taiwanese application no. TW111133781 filed on 09/06/2022. The certified copy of the foreign priority application filed on 09/18/2023 is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 09/05/2023, 03/26/2024, 11/19/2024, and 05/06/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Status of the Claims
Claims 1-20 are pending and being examined on the merits herein.
Drawings
The drawings are objected to because the data as well as the text on the x and y axis and legends shown in Figures 1-5 have poor resolution and legibility.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claim 3 and 20 are objected to because of the following informalities:
Claim 3 recites “… in a granular form, stripe form or a string form.”, which is missing a comma before “or”.
Claim 20 recites “A method for promoting bone regeneration, … , subcutaneous filling and/or treating arthropathy”, which is missing a comma before “and/or”.
Appropriate correction is required.
Claim Interpretation
The recited steps (a) and (b) in instant claim 1 are being interpreted as forming the auto-crosslinked structure, and the recited step (c) is being interpreted as sterilizing via steam treatment the auto-crosslinked HA gel based on the instant specification, which states that the manner of steam treatment is not particularly limited to the present disclosure, provided that the steam treatment is sufficient to convert the auto-crosslinked hyaluronic acid particles into sterile, high viscosity auto-crosslinked hyaluronic acid gels and further states that the time of steam treatment is set based on the steam temperature and the required viscoelastic properties of the gel, provided that the auto-crosslinked hyaluronic acid can be converted from a granular form to a gel form which is sterile while maintaining its crosslinked state (see paragraph 0071 pages 17-18).
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 20 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for promoting bone regeneration, treating bone defects, subcutaneous filling, and/or treating arthropathy, does not reasonably provide enablement for preventing post-operative adhesion The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
To be enabling, the specification of the patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993). Explaining what is meant by “undue experimentation,” the Federal Circuit has stated:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which the experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996).
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Formal, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
1) The breadth of the claims,
2) The nature of the invention,
3) The state of the prior art,
4) The level of one of ordinary skill,
5) The level of predictability in the art,
6) The amount of direction provided by the inventor,
7) The existence of working examples, and
8) The quantity of experimentation necessary
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
The nature of the invention, the breadth of the claims, and relative skill level
The invention relates to a method for promoting bone regeneration, treating bone defects, preventing post-operative adhesion, subcutaneous filling and/or treating arthropathy in a subject in need thereof, comprising administering the auto-crosslinked hyaluronic acid gel of instant claim 15 to the subject in need.
The claims are broad in that they encompass several conditions as well as the prevention of post-operative adhesion.
In the absence of an explicit definition in Applicant’s specification, the claims are given their broadest reasonable interpretation (See MPEP 2111). Institute for International Medical Education (IIME, reference included with PTO-892), defines “prevention” as promoting health, preserving health, and to restore health when it is impaired, and to minimize suffering and distress (see page 16, “Prevention”). IIME further states that “Primary prevention refers to the protection of health by personal and community wide effects, such as preserving good nutritional status, physical fitness, and emotional well-being, immunizing against infectious diseases, and making the environment safe. Secondary prevention can be defined as the measures available to individuals and populations for the early detection and prompt and effective intervention to correct departures from good health. Tertiary prevention consists of the measures available to reduce or eliminate long-term”.
Therefore, in order to give the broadest reasonable interpretation to the claims, “prevention” or "prevent" are thus interpreted to mean that the onset of a condition never occurs and the patient’s health is protected and preserved.
The relative skill of those in the art is high, that of an MD or PHD, someone with experience in the recited conditions/diseases.
The amount of direction or guidance provided and the presence or absence of working examples
Applicant demonstrates in Example 13 (paragraphs 0127-0133 pages 46-49) that their auto-crosslinked hyaluronic acid (HA) gel had better function for bone regeneration than commercially available products (positive control), linear hyaluronic acid gel (control group), and a blank group. The results shown in Figure 6 demonstrate that their HA gels (No. 3-6) had higher percentages of newly formed bone compared to the control groups in a mice test model for bone formation.
However, the instant disclosure does not identify a method that could be used by one of ordinary skill in the art to determine that a subject would have predictably developed post-operative adhesion without the claimed methods in order to establish that the condition was prevented.
The described example suggests that the recited HA gels were effective in promoting bone regeneration and treating the other recited conditions. However, the example does not demonstrate prevention of post-operative adhesion or a predictable method to identify patients who would have developed the post-operative adhesion.
The state and predictability of the art
There are no art recognized methods that could be used to establish that post-operative adhesion was prevented using the therapeutic treatment or to identify patients who would predictably develop post-operative adhesion in order to predictably identify that prevention was achieved using therapeutic approaches. Rather, the art indicates that preventing post-operative adhesion was not predictable.
Arung (in PTO-892) teaches pathophysiology and prevention of postoperative peritoneal adhesions (see Abstract). Arung teaches that postoperative peritoneal adhesions are a major cause of morbidity resulting in multiple complications, many of which may manifest several years after the initial surgical procedure (see Abstract). Arung teaches that development of peritoneal adhesions has been studied extensively, but to date, there has been no definitive strategy to prevent their formation, as controversies concerning the effectiveness of available preventive agents still exist (see left column page 4546). Arung further states that most of the available clinical literature concern gynecological patients; for patients undergoing general and/or abdominal surgery, no recommendations or guidelines exist (see left column page 4546). Arung further states that the exact pathophysiology of peritoneal adhesions has remained elusive and despite many clinical and experimental studies, peritoneal adhesion pathophysiology remains controversial (see left column third paragraph page 4547).
The teachings of Arung demonstrate that despite extensive research into post-operative adhesion, there is still no method that exists to predictably determine how post-operative adhesions are developed, and further that there is no predictable method to prevent this condition.
The quantity of experimentation necessary
Because of the known unpredictability of the art, and in the absence of a predictable method to identify patients who would develop post-operative adhesion without treatment, one of ordinary skilled in the art would not be able to predictably use the claimed HA gel to prevent this condition. Furthermore, the quantity of experimentation to develop a method that could be used to prevent post-operative adhesion would be undue because a method to predictably identify a patient who would get the condition does not exist and as described above, one of ordinary skill would have to further develop this method such that the recited method could then be used as a preventative measure against post-operative adhesion. Accordingly, the instant claims do not comply with the enablement requirement of §112, since to practice the invention claimed in the patent a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1-2, 4-5, 7-9, 11-13 are rejected under 35 U.S.C. 103 as being unpatentable over Cai et al. (Macromolecules, 2017 and supplementary information in PTO-892) in view of Prinz et al. (WO2019238954 A1 in PTO-892).
Cai teaches physically cross-linked hydrogels from hyaluronan (hyaluronic acid or HA) prepared by a freeze-thaw technique at low pH (see Abstract). Cai teaches that the effect of the freezing–thawing of HA solutions on the formation of physical cryogels is typical for the processes of noncovalent cryostructuration that takes the advantages of mild fabrication conditions and the absence of organic solvents and toxic cross-linking agents (see Abstract). Cai teaches their neutral HA cryogels possessed enhanced thermostability, resistance to acid decomposition, and enzyme degradation which are essentially important properties for biomaterials (see Abstract). Cai teaches that HA-based hydrogels hold realized and potential applications in many fields, such as in osteoarthritis treatment, postoperative adhesion prevention, wound dressing, scaffolding materials, drug delivery, and tissue repair and regeneration (see right column page 6647).
Cai discloses their cross-linked HA gels were prepared according to section “Preparation of Acidic and Neutral HA Cryogels” right column page 6648. Here, HA solution was prepared by weighing an amount of HA and adding distilled water at 10 mg/mL, which meets the limitations of a colloid containing hyaluronic acid as recited in instant claim 1 (see instant specification paragraph 0040 page 10, which states “The term “colloid of hyaluronic acid or a metal salt thereof” used herein refers to a colloid formed of solid powder or solid flocculent which swells by absorbing liquid solvent. Examples of the liquid solvent include, but are not limited to, distilled water, deionized water, or saline or buffer solutions.”). Furthermore, the pH of the HA solution was adjusted to 1.5 using 1 M HCl, and then the acidified HA solution was frozen at -20 C for a specified duration, which meets the limitation of an auto-crosslinking of the colloid containing hyaluronic acid in an acidic environment as recited in instant claim 1. Furthermore, 1 M HCl converts to 1 N HCl because normality (N) is related to molarity (M) by the equation N = M x n where n is the number of ionizable hydrogen ions. Here, HCl has a n value of 1 therefore 1 M HCl = 1 N HCl.
Cai further discloses that the acidified HA gels were neutralized by immersing in PBS solution (pH 7) for 6 hours and then further immersed in a large amount of distilled water for 30 minutes (see section “Preparation of Neutral HA Cryogels” right column page 6648), which meets the limitation of washing the product as recited in instant claim 9.
Cai further demonstrates in Figure 2 on page 6650 the rheological properties of HA gels obtained by different freezing times of 3, 6, 9, and 12 days. Cai demonstrates that upon heating the gel from 25 C to 90 C at 5 C / min, the gel formed by freezing for 3 days melted whereas the gels formed by freezing for 6 days and 12 days maintained their network architectures even at 90 C until most of the water evaporated (see right column first paragraph page 6649). Cai discloses that HA gels obtained by freezing for 12 days had a denser structure than that of the gel obtained by freezing for 6 days (right column first paragraph page 6649), and that HA gels obtained by a longer freezing duration had a higher “melting” temperature and thus presented higher thermotolerance similar to cryogels obtained from PVA (see right column first paragraph page 6649). Cai teaches that long freezing time positively contributed to the alignment of polymer chains in the unfrozen liquid microphase, thereby promoting the formation of aggregation that led to high thermotolerant cryogels (see right column first paragraph page 6649), which suggests that freezing times longer than the disclosed 12 days may further increase the thermotolerance of the HA gels.
Cai also demonstrates that the molecular size of the HA can affect the rheological properties (see Table S1 and Fig. S2 in supplementary information and left column last paragraph through right column first paragraph page 6650). Here, Cai discloses their HA gel samples had molecular weights of 25000, 480000, 730000. 1040000, and 1160000 as well as intrinsic viscosity values (dL/g) of 7.23, 12.18, 16.55, 21.31, and 23.11 (see Table S1 and Fig. S2 and left column first paragraph page 6648). Cai discloses that higher molecular weight HA is necessary to form the cryogels as lower molecular weights do not have sufficient molecular chains to entangle together (left column last paragraph through right column first paragraph page 6650). Cai discloses that a higher molecular weight of HA appeared to be conducive to a higher gel-fraction yield, suggesting that at the same concentration a larger molecular size promoted the association of molecular chains as junction zones of network in the gel (see right column first paragraph page 6650). Cai discloses in Fig. S2 that gels with molecular weights greater than 73000 displayed a mechanical spectrum of a comparatively strong gel, with its G′ almost independent of frequency and much higher than G″.
The difference between Cai and the claimed invention is that Cai does not teach step (c) recited in instant claim 1.
Prinz teaches a sterile hydrogel composition comprising crosslinked thiol-modified hyaluronan (see Abstract). Prinz teaches that their hydrogel composition is sterile and may be used as a medicine, cosmetic or medical device (page 19 lines 28-29). Prinz teaches that the hydrogel can be implanted by injection (page 19 lines 30-31) and that the hydrogel can be filled in a syringe that is further sterilized (see page 10 lines 23-24). Prinz teaches that the term “sterile” is understood to be a composition complying with the microbiological standards as defined for cosmetic or pharmaceutical products, for example in the United States Pharmacopoeia (USP), and that thermal moist-heat sterilization with an autoclave is a standard method, which comprising subjecting the HA gels to high-pressure saturated steam at 121 C for around 15-20 minutes (see page 17 lines 5-15). Prinz teaches that autoclaving parameters can be optimized such as shorter time periods (1 to 5 minutes) or higher temperatures (130-135C) in order to preserve the molecular weight of the HA molecules in the gels (see page 17 lines 11-20).
It would have been prima facie obvious before the effective filing date of the claimed invention to have modified the HA gel disclosed in Cai by further sterilizing the HA gel by subjecting the gel to high-pressure saturated steam at 121 C for 15-20 minutes as disclosed in Prinz to arrive at the claimed invention. One of ordinary skill in the art would have made motivated to make this modification because Prinz provides further guidance of sterilizing HA gels under certain standards such as USP in order to be used as a medical product. One of ordinary skill in the art would have reasonable expectation of success to make this modification because Cai demonstrates that heating HA gels with longer freezing durations such as 12 days had higher thermostability and thermotolerance.
In regards to instant claim 12, even though the combined teachings described above do not teach a pH range of about 6.3 to about 6.8, MPEP 2144.05 I recites “a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close” and “under the doctrine of equivalents, a purification process using a pH of 5.0 could infringe a patented purification process requiring a pH of 6.0-9.0”. Here, Cai teaches a step of neutralizing the acidic HA gel using a PBS solution of pH 7. Therefore, the pH of 7 taught in Cai is merely close to the recited range in instant claim 12 such that a prima facie case of obviousness exists.
Claim(s) 3 is rejected under 35 U.S.C. 103 as being unpatentable over Cai et al. (Macromolecules, 2017 in PTO-892) in view of Prinz et al. (WO2019238954 A1 in PTO-892), as applied to claim 1 above, and further in view of Karlsson et al. (US20160145357A1 in PTO-892).
The combined teachings of Cai and Prinz are as described above and teach the method of instant claim 1 as discussed above.
The combined references, however, do not teach wherein step (a) comprises providing the colloid containing hyaluronic acid in a granular form, a stripe form, or a string form.
Karlsson discloses a method for making shaped cross-linked hyaluronic acid products (see Abstract). Karlsson discloses that known soft-tissue augmentation treatments involving implants occasionally suffer from the drawback that the implant, or part thereof, migrates away from the desired site of treatment (paragraph 0011), and that their cross-linked hyaluronic acid product has a shape that restricts the possibility for the product to migrate following implantation into a subject (paragraph 0012).
Karlsson disclose their method involves a step of first (i) providing a hyaluronic acid substrate dissolved in a first liquid medium without any cross-linking, then (ii) precipitating the hyaluronic acid substrate by subjecting it to a second liquid medium comprising an amount of one or more first water-soluble organic solvent(s) giving precipitating conditions for hyaluronic acid without any cross-linking; wherein step (i) and/or step (ii) further comprises arranging the hyaluronic acid substrate in a desired shape (paragraphs 20-21), and finally (iii) subjecting the non-cross-linked precipitated hyaluronic acid substrate in the desired shape to a single cross-linking step (paragraph 0022).
Karlsson discloses that the desired shape can be a particle, a fibre, a string, a strand, a net, a film, a disc and a bead (paragraph 0029). Karlsson discloses that it is important to ensure that cross-linking does not occur until the preferred shape has been attained, and that it is advantageous for obtaining and maintaining a desired shape of the final product, since the shaping of the substrate is not limited by pre-existing cross-links, and all cross-links produced in the third step are directed to maintaining the desired shape of the product (paragraph 0087).
It would have been prima facie obvious before the effective filing date of the claimed invention to have modified the HA gel forming method as taught in the combined teachings of Cai and Prinz described by shaping the HA colloid solution into a string form as disclosed in Karlsson before performing the freeze thaw crosslinking step to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to make this modification because Karlsson provides guidance of shaping HA gels to avoid implant migration from treatment site and also shaping the HA before crosslinking to not limit the desired shape from pre-existing cross-links. One of ordinary skill would have a reasonable expectation of success in making this modification because Karlsson provides guidance that the shaping of the HA can be performed before any cross-linking step is performed.
Claim(s) 6 is rejected under 35 U.S.C. 103 as being unpatentable over Cai et al. (Macromolecules, 2017 in PTO-892) in view of Prinz et al. (WO2019238954 A1 in PTO-892), as applied to claims 1 and 5 above, and further in view of CN106110369 B (in PTO-892, an English translation is provided and used as the basis for this rejection).
The combined teachings of Cai and Prinz are as described above and teach the method of instant claims 1 and 5 as discussed above.
The combined references, however, do not teach wherein the concentration of hyaluronic acid in the mixture is 10-30 wt%.
CN’369 teaches a medical composite hyaluronic acid dressing and its preparation method (paragraph 0002). CN’369 teaches that their composite comprises a hyaluronic acid (HA) – polyvinyl alcohol (PVA) gel that takes advantage of the strong water absorption and good biocompatibility of hyaluronic acid to provide a moist environment for acne and other skin surface wounds (paragraph 0009).
CN’369 teaches that the amounts in their HA-PVA gel are 15-30% HA and 70-85% PVA (paragraph 0013-0018). CN’369 teaches that their HA-PVA gels are formed by first mixing and dissolving HA and PVA in purified water (paragraph 0045) and then performing several freeze-thaw cycles where the mixed solution is frozen at -20 C for 24 hours and then thawed at room temperature for 12 hours (paragraph 0045).
It would have been prima facie obvious before the effective filing date of the claimed invention to have modified the amount of HA in the HA gel as taught in the combined teachings of Cai and Prinz described above to be 15-30% wt HA as disclosed in CN’369 to arrive at the claimed invention. One of ordinary skill in the art would have made this modification with a reasonable expectation of success because CN’369 provides guidance that this wt% range for HA is suitable for forming a HA gel using a similar freeze-thaw gel formation method as the freeze-thaw method disclosed in Cai.
Claim(s) 10 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Cai et al. (Macromolecules, 2017 in PTO-892) in view of Prinz et al. (WO2019238954A1 in PTO-892), as applied to claim 1 above, and further in view of JP2000191702A (in PTO-892, an English translation is provided and used as the basis for this rejection) and CN106110369B (in PTO-892, an English translation is provided and used as the basis for this rejection).
The combined teachings of Cai and Prinz are as described above and teach the method of instant claims 1 as discussed above.
The combined references, however, do not teach wherein the product of step (b) has an equilibrium swelling capacity of about 12 to about 30 as well as one of the recited properties for the HA gel in instant claim 14.
JP’702 teaches a method for producing a molded article having in vivo storage properties, particularly a sheet, which is suitable as a medical material, particular as an adhesion preventing material and a wound covering material (see Abstract). JP’702 teaches that the method comprises freezing and thawing an acidic aqueous solution of HA (paragraph 0009), and that the freezing temperature ranges from -30 C to -10 C (paragraph 0009).
The teachings of CN’369 are as described above.
It would have been prima facie obvious before the effective filing date to have modified the HA gel as taught in the combined teachings of Cai and Prinz described above by performing longer freezing times greater than 12 days to form the gel as suggested by Cai, a freezing temperature between -30 C to -10 C as taught by JP’702, and to have an HA content of 15-30% wt as taught by CN’369 as well as using a starting HA material having a molecular between 730000-1160000 and intrinsic viscosity values between 1.655-2.311 m3/kg as disclosed in Cai to arrive at the claimed invention. One of ordinary skill in the art would have motivated to perform longer duration of freezing times past 12 days because Cai discloses that longer freezing times to form the HA gel resulted in increased thermotolerance which may be beneficial for biomaterial applications. One of ordinary skill in the art would have a reasonable expectation of success because Cai discloses that gels formed from 12 days of freezing had higher thermotolerance than gels formed from 6 days of freezing. Furthermore, one of ordinary skill in the art would have made the modifications of performing the freezing temperatures between -30 to -10C as well as forming an HA gel having 15-30% HA with a reasonable expectation of success because JP’702 provides guidance that a freezing temperature ranging from -30 to -10 C is suitable for forming the same HA gel using the freeze-thaw method, and CN’369 also provides guidance that this wt% range for HA is suitable for forming a similar HA gel using the same freeze-thaw gel formation method. One of ordinary skill in the art would have been motivated to use a starting HA with the described molecular weights because Cai suggests that higher molecular weight HA gels promoted the association of molecular chains as junction zones of network in the gel. One of ordinary skill in the art would have a reasonable expectation of success because Cai demonstrates that HA gels with molecular weights greater than 730000 displayed a mechanical spectrum of a comparatively strong gel, with its G′ almost independent of frequency and much higher than G″.
Lastly, the recited equilibrium swelling capacity range recited instant claim 10 as well as the properties for the HA gel disclosed in instant claim 14 would be necessarily present in the HA gel as taught in the combined teachings of Cai, Prinz, JP’702, and CN’369 described above because the combined references teach the same method of producing an HA gel that has the same HA amounts (15-30%), freezing temperatures (-30 to -10 C), reaction times (greater than 12 days), HCl concentration mixture (1 N), steam treatment (121 C for 15-20 minutes), and pH (7) as the HA gels shown in Example 2 Table 2 (paragraph 0094) and Table 13 of the instant specification (paragraph 0126). Furthermore, the combined teachings of Cai, Prinz, JP’702, and CN’369 described above discloses using a starting HA having molecular weights between 730000-1160000 with intrinsic viscosities between 1.655-2.311 m3/kg, which overlaps with the HA used in the instant specification (molecular weight between 983000 to 1121000 and intrinsic viscosities between about 1.7 to about 2.0 m3/kg – see paragraph 0046 on page 12).
The HA gels in Table 2 and Table 13 (Example 2) had a HA content of 14.5 wt% and formed using reaction temperature of -20 C and duration of 14, 21, 28 days, 1 N HCl, 121 C steam treatment for 10-40 minutes, and pH 7. Table 2 and 13 further discloses that HA gels formed with these parameters has the recited properties in the instant claims, and the combined references described above teach all of these parameters to form the HA gel using the same freeze-thaw method.
MPEP 2112 section I recite "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable”. Furthermore, MPEP 2112.01 section II recites “Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.”
Claim(s) 15-20 are rejected under 35 U.S.C. 103 as being unpatentable over Cai et al. (Macromolecules, 2017 in PTO-892) in view of Prinz et al. (WO2019238954A1 in PTO-892), JP2000191702A (in PTO-892, an English translation is provided and used as the basis for this rejection) and CN106110369B (in PTO-892, an English translation is provided and used as the basis for this rejection).
The teachings of Cai are as described above.
The teachings of Cai, however, do not teach an auto-crosslinking HA gel having the properties recited in instant claims 15-19.
The independent teachings of Prinz, JP’702, and CN’369 are as described above.
It would have been prima facie obvious before the effective filing date of the claimed invention to have modified the HA gel disclosed in Cai by performing longer freezing times greater than 12 days to form the gel as suggested by Cai, further sterilizing the HA gel by subjecting the gel to high-pressure saturated steam at 121 C for 15-20 minutes as disclosed in Prinz, using a freezing temperature between -30 C to -10 C as taught by JP’702, and to have an HA content of 15-30% wt as taught by CN’369 as well as using a starting HA material having a molecular between 730000-1160000 and intrinsic viscosity values between 1.655-2.311 m3/kg as disclosed in Cai to arrive at the claimed invention to arrive at the claimed invention. One of ordinary skill in the art would have made the modification of sterilizing the HA gel with a reasonable expectation of success because both Cai and Prinz teach the use of HA gels for various medical application such as a wound dressing material, and Prinz provides further guidance of sterilizing HA gels under certain standards such as USP in order to be used as a medical product. Furthermore, one of ordinary skill in the art would have motivated to perform longer duration of freezing times past 12 days because Cai discloses that longer freezing times to form the HA gel resulted in increased thermotolerance which may be beneficial for biomaterial applications. One of ordinary skill in the art would have a reasonable expectation of success because Cai discloses that gels formed from 12 days of freezing had higher thermotolerance than gels formed from 6 days of freezing. Furthermore, one of ordinary skill in the art would have made the modifications of performing the freezing temperatures between -30 to -10C as well as forming an HA gel having 15-30% HA with a reasonable expectation of success because JP’702 provides guidance that a freezing temperature ranging from -30 to -10 C is suitable for forming the same HA gel using the freeze-thaw method, and CN’369 also provides guidance that this wt% range for HA is suitable for forming a similar HA gel using the same freeze-thaw gel formation method. One of ordinary skill in the art would have been motivated to use a starting HA with the described molecular weights because Cai suggests that higher molecular weight HA gels promoted the association of molecular chains as junction zones of network in the gel. One of ordinary skill in the art would have a reasonable expectation of success because Cai demonstrates that HA gels with molecular weights greater than 730000 displayed a mechanical spectrum of a comparatively strong gel, with its G′ almost independent of frequency and much higher than G″.
Lastly, the properties recited in instant claims 15-19 for the HA gel would be necessarily present in the HA gel as taught in the combined teachings of Cai, Prinz, JP’702, and CN’369 described above because the combined references teach the same method of producing an HA gel that has the same HA amounts (15-30%), freezing temperatures (-30 to -10 C), reaction times (greater than 12 days), HCl concentration mixture (1 N), steam treatment (121 C for 15-20 minutes), and pH (7) as the HA gels shown in Example 2 Table 2 (paragraph 0094) and Table 13 of the instant specification (paragraph 0126). Furthermore, the combined teachings of Cai, Prinz, JP’702, and CN’369 described above discloses using a starting HA having molecular weights between 730000-1160000 with intrinsic viscosities between 1.655-2.311 m3/kg, which overlaps with the HA used in the instant specification (molecular weight between 983000 to 1121000 and intrinsic viscosities between about 1.7 to about 2.0 m3/kg – see paragraph 0046 on page 12).
The HA gels in Table 2 and Table 13 (Example 2) had a HA content of 14.5 wt% and formed using reaction temperature of -20 C and duration of 14, 21, 28 days, 1 N HCl, 121 C steam treatment for 10-40 minutes, and pH 7. Table 2 and 13 further discloses that HA gels formed with these parameters has the recited properties in the instant claims, and the combined references described above teach all of these parameters to form the HA gel using the same freeze-thaw method.
MPEP 2112 section I recite "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable”. Furthermore, MPEP 2112.01 section II recites “Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.”
In regards to instant claim 20, it would have also been prima facie obvious before the effective filing date of the claimed invention to have administered the HA gel as taught in the combined teachings of Cai, Prinz, JP’702, and CN’369 described above for treating the recited conditions in instant claim 20. One of ordinary skill in the art would have made this modification with a reasonable expectation of success because Cai provides guidance that that HA-based hydrogels hold realized and potential applications in many fields, such as in osteoarthritis treatment, postoperative adhesion prevention, wound dressing, scaffolding materials, drug delivery, and tissue repair and regeneration.
Conclusion
No claim is found allowable.
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/D.H.C./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693