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.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.
Applicant's submission filed on 01/21/2026 has been entered.
Priority
The instant application is a 371 of PCT/EP2021/051394 filed on 01/21/2021, which claims
foreign priority to European application no. EP20305051.3 filed on 01/22/2020. The certified copy for
EP20305051.3 has been filed on 06/28/2022 in the instant application.
Status of the Claims
The claim amendments and remarks filed on 01/21/2026 is acknowledged. Claims 1-20, 24, 30, and 32-24 are cancelled. Claims 21, 25, and 31 are amended.
Accordingly, claims 21-23, 25-29, 31, and 35-38 are pending and being examined on the merits herein.
Withdrawn Rejections
The cancellation of claims 24, 30, and 32 renders the 35 USC 103 rejection over Molliard in view of Daar moot.
The cancellation of claims 33-34 renders the 35 USC 103 rejection over Molliard in view of Daar and Hunter moot.
The 35 USC 103 rejections over Molliard in view of Daar, Molliard in view of Daar and Willey, and Molliard in view of Daar and Hunter are withdrawn in favor of the rejections set for below.
The following grounds of rejections are new.
Specification
The disclosure is objected to because of the following informalities:
Page 5 lines 23-24 recites “… preferably between 105 and 4.105 and very preferably between 5.105 and 2.106 Da.”
The values recited for the molecular weights are not conventional, and is suggested to be changed to “between 105 and 4 x 105 …” and “between 5 x 105 and 2 x 106 Da”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 25 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 25 recites “… a molecular weight between 5.105 and 2.106 Da.”
Claim 25 is indefinite because it is not clear if the molecular weight range is between 5.105 and 2.106 Da, which would be outside of the molecular weight range recited in claim 21 (claim 25 depends from claim 21), of if the molecular weight range was meant to be between 5 x 105 and 2 x 106 Da, which would be within the range recited in claim 21.
For purposes of examination, claim 25 is being interpreted as a molecular weight between 5 x 105 and 2 x 106 Da.
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) 21, 25-29, 31, and 35 are rejected under 35 U.S.C. 103 as being unpatentable over Daar et al. (Radiation Physics and Chemistry, 2017 in PTO-892 dated 10/27/2025) in view of Molliard et al. (EP3498262A1 in PTO-892 dated 05/16/2025), English translation provided and used as for the basis for this rejection).
Daar et al. discloses the effects of radiotherapy doses on the extracellular matrix such as hyaluronic acid (HA) and pericardium (see Abstract). Daar discloses that HA is a major component in the synovial fluid of articulating joints and plays a dominant role in joint lubrication (see right column second paragraph page 177). Daar discloses that HA is the major determinant of viscoelastic behavior in synovial fluid, and that because the body will begin to lose the ability to produce HA, it is important to understand what effects irradiation such as in radiotherapy of joints can have on HA with loss in viscosity and wear resistance being expected to impact upon the quality of life. (see right column second paragraph page 177). Daar discloses that irradiation in the aqueous state involves action of free radicals, where H* and OH* radicals interact with the surrounding molecules in solution (see last paragraph page 178 left column to top right column). Daar discloses that irradiation of HA will result in ionization and excitation of the atoms of HA and surrounding ECM, leading to changes in the physical and chemical nature of polymeric HA such as simultaneous chain scission and cross-linking, bond deformation, and reduction of the molecular weight and associated viscosity (see right column last paragraph page 177). Daar discloses that chemical degradation of HA induced by reactive oxygen-derived species has attracted considerable attention in regard to HA depolymerization. Therefore, Daar suggests irradiation induced depolymerization or bond deformation at low-levels of irradiation dose should be investigated (see right column last paragraph page 177 through left column first paragraph page 178).
The difference between Daar and the claim invention is that Daar does not administering the recited composition to protect HA from ionizing radiation degradation.
Molliard et al. discloses a sterile injectable aqueous formulation in gel form composed of hyaluronic acid (or one of its salts) with or without other polysaccharide(s) of natural origin and of one or more polyol(s) (see translated paragraph 0001). Molliard et al. discloses that their injectable formulation is used in intra-articular mode in the treatment of articular degeneration (see paragraph 0001) as well as viscosupplementation to the joints (see paragraph 0006). Molliard discloses that viscosupplementation involves injecting a gel into the joint in order to replace deficient synovial fluid and help attenuate or block pain and contribute to restoring joint mobility (paragraph 0006). Molliard discloses that the persistence of HA gels in joints are low due to the degradation of the HA from factors including radical, thermal, mechanical degradation (paragraph 0009). Molliard discloses that increasing the residence time of a HA gel in the joint will help increase its viscosupplementation efficiency and improve the overall effectiveness of the gel (paragraph 0009-0010).
Molliard et al. discloses that the addition of polyol to a hyaluronic acid-based gel unexpectedly and significantly increased the resistance to degradation of the gel (see paragraph 0011) and demonstrates in Example 4 the resistance of a gel based on hyaluronic acid and a polyol when subject to a radical, thermal, and mechanical degradation test. Molliard et al. discloses several exemplary formulations comprising 15-20 mg/ml (1.5- 2% w/v) hyaluronic acid with an average molecular weight of 2.5 x 106 Da and a polyol such as 20 mg/ml (2% w/v) glycerol, 15 mg/ml (1.5 % w/v) propylene glycol, 15 mg/ml (1.5 % w/v) mannitol, and 40-50 mg/ml (4-5 % w/v) sorbitol (see paragraph 0040). Here, Formulation E disclosed in paragraph 0040 contains 18 mg/mL of hyaluronic acid and 50 mg/mL of sorbitol, which equates to a ratio between hyaluronic acid and sorbitol of 0.36:1. Molliard et al. demonstrates that these formulations were able to resist radical degradation from an oxidant (oxidative stress) (see paragraph 00470051). Molliard et al. discloses that the molecular weight of the hyaluronic acid can be between 0.1 x 106 Da to 10 x 106 Da (see paragraph 0023). Molliard et al. discloses that the concentration of the hyaluronic acid can be between 1 and 100 mg/mL (0.1% - 10% w/v) (see paragraph 0024).
It would have been prima facie obvious before the effective filing date of the claimed invention to have treated the joints of patients undergoing ionizing radiation-based treatments as disclosed in Daar by using the gel composition of Molliard for viscosupplementation as disclosed in Molliard to arrive at the claimed invention. One of ordinary skill in the art would have considered making this modification with a reasonable expectation of success because Daar establishes a need to investigate the effects that ionizing radiation from radiotherapy has on the HA in articulating joints and further discloses that ionizing radiation exposure involves the action of free radicals in aqueous environment, which can degrade HA from ionization and excitation of the atoms of HA and surrounding ECM and lead to a loss in its important properties such as its viscoelastic behavior in the synovial joint. Furthermore, Molliard discloses the use of their HA compositions for viscosupplementation to the joints as well as providing protection against degradation induced by radicals such as oxidative stress. Therefore, the teachings of Daar, which disclose HA degradation and loss of viscoelastic behavior in the joints induced by ionizing radiation exposure, would have led an ordinary skilled artisan to consider with a reasonable expectation of success in using the HA compositions of Molliard, which are useful for viscosupplementation of the joints and provides protection from degradation induced by radical exposure.
Furthermore, even though the combined teachings of Daar and Molliard do not experimentally demonstrate that the HA would be protected against ionizing radiation degradation by using the recited HA compositions, an ordinary skilled artisan would have reasonably expected that the compositions of Molliard would also provide protection from ionizing radiation degradation because Daar discloses that ionizing radiation involves the interaction of free radicals in aqueous environment on surrounding molecules such as HA, and Molliard discloses that their HA compositions provide protection against degradation induced by radical exposure. Furthermore, this recited protection would flow naturally from the combined teachings because the combined teachings suggest administering the same amount and molecular weight ranges of HA as well as same amount ranges of polyols into the joints of a patient that is exposed to ionizing radiation in these joints. The HA compositions of Molliard contain the same range of MW and amounts of HA as well as amounts of mannitol, glycerol, or sorbitol as disclosed in the Table on page 13 of the instant specification.
MPEP 2145 II recites “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter.m 1985) (The prior art taught combustion fluid analyzers which used labyrinth heaters to maintain the samples at a uniform temperature. Although appellant showed that an unexpectedly shorter response time was obtained when a labyrinth heater was employed, the Board held this advantage would flow naturally from following the suggestion of the prior art.). See also Lantech Inc. v. Kaufman Co. of Ohio Inc., 878 F.2d 1446, 12 USPQ2d 1076, 1077 (Fed. Cir. 1989), cert. denied, 493 U.S. 1058 (1990) (unpublished — not citable as precedent) ("The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.").”
In regards to instant claims 25 and 31, it would have also been prima facie obvious to prepare the HA composition described above with a molecular weight between 5 x 105 Da and 2 x 106 Da as well as between 0.05% and 1% of the total weight of the composition based on the teachings of Molliard. One of ordinary skill in the art would have made these modifications with a reasonable expectation of success because Molliard et al. teaches an overlapping molecular weight of 0.1 x 106 Da to 10 x 106 Da as well as an overlapping weight percent of 0.1% - 10% w/v. See MPEP 2144.05 I.
Claim(s) 22 are rejected under 35 U.S.C. 103 as being unpatentable over Daar et al. (Radiation Physics and Chemistry, 2017 in PTO-892 dated 10/27/2025) in view of Molliard et al. (EP3498262A1 in PTO-892 dated 05/16/2025), English translation provided and used as for the basis for this rejection), as applied to claim 21 above, and further in view of Willey et al. (Int. J. Radiat. Bio., 2013 in PTO-892 dated 10/27/2025).
The combination of Daar and Molliard teaches the method of claim 21 as discussed above.
The difference between the combination of Daar and Molliard and the claimed invention is that the combination of Daar and Molliard does not disclose an ionizing radiation from gamma or beta types.
Willey discloses active degradation and reduced matrix synthesis in joint articular cartilage caused by ionizing radiation (see Abstract). Willey discloses that joint damage has been reported following cancer treatment or occupational exposures (see Abstract and first paragraph under “Introduction”, pages 1-2). Willey et al. discloses that exposure to 2 Gy and 10 Gy doses of ionizing radiation lowered proteoglycan synthesis, induced active degradation of matrix, and impaired IGF-1 signaling in human and pig cartilage and chondrocytes (see second paragraph page 9). Willey et al. discloses that the ionizing radiation used in their experiments was conducted using a 137Cs irradiator, which generates gamma radiation (see last paragraph page 3). Willey et al. discloses that weakening of articular cartilage through persistent radiation-induced changes in matrix metabolism or permanent deterioration of mechanical properties could contribute to arthropathy following direct irradiation (see last paragraph page 9).
It would have been prima facie obvious before the effective filing date of the claimed invention that the patient population disclosed in the combined teachings of Daar and Molliard described above can also include patients exposed to gamma radiation as disclosed in Willey. One of ordinary skill in the art would have made this modification with a reasonable expectation of success because both Daar and Willey disclose that ionizing radiation such as its use in radiotherapy can cause degradation of the matrix in joints.
Claim(s) 23 and 36-38 are rejected under 35 U.S.C. 103 as being unpatentable over Daar et al. (Radiation Physics and Chemistry, 2017 in PTO-892 dated 10/27/2025) in view of Molliard et al. (EP3498262A1 in PTO-892 dated 05/16/2025), English translation provided and used as for the basis for this rejection), as applied to claim 21 above, and further in view of Hunter et al. (US20060040894A1 in IDS filed on 06/28/2022).
The combined teachings of Daar and Molliard teach the method of claim 21 as discussed above. Furthermore, Molliard et al. discloses that the hyaluronic acid composition may also include polysaccharide of natural origin such as cellulose and derivatives thereof and among others (see paragraph 0025). Molliard et al. discloses both the hyaluronic acid as well as the additional polysaccharide may be crosslinked or non-crosslinked, grafter or non-grafted according to the crosslinking/grafting techniques described in the prior art (see paragraph 0026).
The difference the combined teachings of Daar and Molliard and the claimed invention is that the combined teachings of Daar and Molliard do not disclose a composition that further comprises carboxymethyl cellulose in the recited amounts.
Hunter et al. discloses compositions and devices including hyaluronic acid (HA) and a compound that inhibits degradation of hyaluronic acid, and methods of making and using same (see Abstract). Hunter et al. discloses their compositions may be utilized for a variety of clinical indications including viscosupplementation in joints and among others (see paragraph 0017). Hunter et al. exemplifies in Examples 1-4 that the addition of various compounds such as propylene glycol, polyethylene glycol, or carboxymethylcellulose to a HA-based gel inhibits the enzymatic degradation action of hyaluronidases (see paragraph 246-250 and Fig. 4 and 7). Hunter et al. discloses the test compositions comprised of 0.07% hyaluronic acid and either 10 mg/ml (1% w/v) propylene glycol or 10mg/ml (1% w/v) carboxymethylcellulose (see paragraph 250, Table 4).
It would have been prima facie obvious to before the effective filing date of the claimed invention by selecting 1% w/v carboxymethylcellulose as disclosed in Hunter et al. for the additional polysaccharide that can be included in the modified composition of Daar and Molliard described above to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to make this modification because Hunter discloses that the addition of carboxymethylcellulose can provide protection against enzymatic degradation action from hyaluronidases. One of ordinary skill in the art would have a reasonable expectation of success because Molliard et al. establishes that their compositions can include additional polysaccharides and lists cellulose and its derivatives, and Hunter et al. provides further guidance of using carboxymethyl cellulose (a cellulose derivative) in a similar hyaluronic acid based gel for a similar purpose of protecting the hyaluronic acid from degradation as well as for the same application of viscosupplementation to joints.
In regards to instant claims 36-38, it would have also been prima facie obvious before the effective filing date of the claimed invention to have used 0.07% hyaluronic acid and 1% carboxymethylcellulose as disclosed in Hunter for the hyaluronic acid and carboxymethylcellulose disclosed in the combined teachings of Daar, Molliard, and Hunter described above to arrive at the claimed ratio between the hyaluronic acid and carboxymethylcellulose. One of ordinary skill in the art would have made this modification with a reasonable expectation of success because Hunter demonstrates these weight percentages, which read on the recited ratio, is effective for protecting hyaluronic acid from degradation.
Response to Arguments
Applicant’s arguments filed on 01/21/26 have been fully considered in so far as they apply to
the rejections of the instant office action, but were not persuasive.
Applicant states that the combination of Molliard and Daar relies on impermissible hindsight reconstruction. Applicant states that Molliard only discloses the use of their compositions for protection against HA degradation under radical, thermal, and mechanical stress and not for degradation caused by ionizing radiation. Applicant states that the deficiencies of Molliard is not remedied by Daar, which discloses the effects of ionizing radiation in the ECM, particularly HA, in articular joints. Applicant states there is no motivation or suggestion in Daar to combine with Molliard and that neither Daar nor Molliard suggests that HA compositions of Molliard would also provide protection against degradation induced by ionizing radiation.
Applicant’s arguments described above were not persuasive because the teachings of Daar, which disclose HA degradation and loss of viscoelastic behavior in the joints induced by ionizing radiation exposure, would have led an ordinary skilled artisan to consider with a reasonable expectation of success in using the HA compositions of Molliard, which are useful for viscosupplementation of the joints and provides protection from degradation induced by radical exposure. Therefore, the new rejection over Daar in view of Molliard does not rely on impermissible hindsight reconstruction to arrive at the claimed invention.
Furthermore, even though the combined teachings of Daar and Mollaird do not experimentally demonstrate that the HA would be protected against ionizing radiation degradation by using the recited HA compositions, an ordinary skilled artisan would have reasonably expected that the compositions of Molliard would also provide protection from ionizing radiation degradation because Daar discloses that ionizing radiation involves the interaction of free radicals in aqueous environment on surrounding molecules such as HA, and Molliard discloses that their HA compositions provide protection against degradation induced by radical exposure. Furthermore, this recited protection would flow naturally from the combined teachings because the combined teachings suggest administering the same amount and molecular weight ranges of HA as well as same amount ranges of polyols into the joints of a patient that is exposed to ionizing radiation in these joints. The HA compositions of Molliard contain the same range of MW and amounts of HA as well as amounts of mannitol, glycerol, or sorbitol as disclosed in the Table on page 13 of the instant specification.
MPEP 2145 II recites “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter.m 1985) (The prior art taught combustion fluid analyzers which used labyrinth heaters to maintain the samples at a uniform temperature. Although appellant showed that an unexpectedly shorter response time was obtained when a labyrinth heater was employed, the Board held this advantage would flow naturally from following the suggestion of the prior art.). See also Lantech Inc. v. Kaufman Co. of Ohio Inc., 878 F.2d 1446, 12 USPQ2d 1076, 1077 (Fed. Cir. 1989), cert. denied, 493 U.S. 1058 (1990) (unpublished — not citable as precedent) ("The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.").”
Applicant further states that Molliard does not teach the use of their compositions addressed by the instant invention, which is to provide an effective solution for protecting against HA against ionizing radiation degradation such as sterilization processes or manufacturing of medical devices. Applicant states that the context and basis of HA degradation of HA is entirely different in the teachings of Molliard, and therefore a direct comparison with the specific formulations of Molliard are not required. Applicant states that the examples in the instant specification and the Declaration filed on 08/07/2025 demonstrate that the recited HA compositions were effective in protecting against ionizing radiation degradation.
In response to Applicant’s argument that the references fail to shown certain features of the invention, it noted that the features upon which Applicant relies (i.e., ionizing radiation degradation during a process of sterilization or manufacturing of medical devices) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Therefore, the combined teachings of Daar and Molliard as described above still meet all of the limitations of the instant claims.
In regards to comparing to the closest prior art, MPEP 716.02(e) states that “An affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness”. Here, while a comparison to the methods of Molliard are not required, a comparison to the HA formulations of Molliard is still required in order to determine if Applicant’s composition in the recited method provides an unexpected result of protecting HA from damage caused by ionizing radiation over the compositions disclosed in Molliard. Since this comparison to the formulations of Molliard has not been provided, the current showing of unexpected results is not sufficient to overcome the closest prior art (Molliard).
Lastly, it is noted that MPEP 2144.05 III A states “Applicants can rebut a prima facie case of obviousness by showing the criticality of the range. "The law is replete with cases in which the difference between the claimed invention and the prior art is some range or other variable within the claims. . . . In such a situation, the applicant must show that the particular range is critical, generally by showing that the claimed range achieves unexpected results relative to the prior art range."
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