Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
This Office Action is in response to Applicants’ Amendment and Remarks filed on 1/14/2026 in which claims 4, 5, and 7 are amended. No claims are newly added or canceled. In addition, claims 1-3 and 10-13 remain withdrawn as be directed towards non-elected invention.
Claims 1-13 are pending in the instant application.
Claims 4-9 are examined on the merits herein.
Priority
This application is a National Stage Application of PCT/CN2020/091956, filed on 5/23/2020. The instant application claims foreign priority to CN 201911331251.7 filed on 12/21/2019. Acknowledgment is made of applicant's claim for foreign priority under 35 U.S.C. 119(a)-(d). The certified copy has been filed in the instant application on 6/23/2025. The English translation and statement of translation accuracy, of the certified copy of the foreign priority document, was made of record on 1/14/2026. Thus foreign priority has been perfected. The effective filing date of the instant application is 12/21/2019.
Withdrawn Rejections
Applicant’s amendment, filed on 1/14/2026, with respect to the rejection of claims 4-6, 8 and 9 under 35 U.S.C. 112(a), for lack of enablement has been fully considered and is persuasive. Applicants’ amendment narrowed the scope of the claims to be fully enabled by the specification. The rejection is hereby withdrawn.
Applicant’s amendment, filed on 1/14/2026, with respect to the rejection of claims 4-9 under 35 U.S.C. 112(b), for indefiniteness of “narrow” and “preferably”, has been fully considered and is persuasive. Applicants’ amendment removed references to “narrow” and “preferably”. The rejection is hereby withdrawn.
Maintained Rejections
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 4-8 are rejected under 35 U.S.C. 103 as being unpatentable over Lv et al. (Carb. Poly., 2016, reference of record) and Yuan et al. (Carb. Poly., 2015, reference of record).
Lv et al. discloses a process for preparing a mixture of hyaluronic acid oligosaccharides by incubating one gram hyaluronic acid of molecular weight 1.21x10^6 Da, in 100 mL distilled water, with leech hyaluronidase derived from P. pastoris (LHase; 4000-32000 U/mL), at 38°C for 0.5 to 40 hours, followed by boiling to terminate enzymatic activity. (Sec. 2.1-2.2) Lv further discloses that a homologous series of even-numbered oligosaccharides were quickly produced by LHase and the major products were HA4 and HA6, where hyaluronic acid disaccharides, tetrasaccharides, hexasaccharides and octasaccharies were observed. (Figure 1, Figure 3, p. 312) While oligosaccharides larger than octasaccharides are not explicitly identified by Lv, it is noted that in Figure 1A, signals are seen at retention times of 30, 40 and 60 minutes, that would reasonably correspond to decasaccharides, dodecasaccharides and tetradecasaccharides, respectively, in view of Lv teaching a homologous series of even-numbered oligosaccharides.
Yuan et al. discloses a process for preparing a mixture of hyaluronic acid oligosaccharides by incubating hyaluronic acid (40 g/L) of molecular weight 1.21x10^6 Da, in 2L distilled water, with leech hyaluronidase derived from P. pastoris (HAase; 1.20x10^6 U/mL), at 45°C and pH 6.5 for 0 to 24 hours, with stirring at 500 RPM. (Sec. 2.2, 3.1, 3.2; Figure 1) Yuan further discloses that in particular, 6.00 × 104U/mL HAase was added to the hydrolysis system containing 40 g/L HA. MALDI-TOF MS spectrometry was applied for analyzing the degradation products. At 0.5 h, trace amounts of HA oligomers HA10, HA8, HA6, and HA4 were generated. When the incubation period was extended to 5.5 h, HA10 was completely converted to HA6 and HA4. At 6.5 h, the peak corresponding to HA8 disappeared and only two ion peaks corresponding to HA6 and HA4 were detected, indicating that all the higher HA oligomers were exhaustively digested to the end products HA6 and HA4. Moreover, it has been demonstrated that the reducing end of HA oligomers from leech HAase was glucuronic acid. (p. 199, Col. 2; Figure 4) Yuan also discloses that the polydispersity of the digested hyaluronic acid product using HAase was low as seen in Tables 1 and 2.
Neither Lv nor Yuan individually teaches that the hyaluronidase digestion process results in obtaining the claimed mixture of hyaluronic acid oligosaccharides, in the claimed percentages.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that taking the disclosure of Lv and Yuan collectively that a leech hyaluronidase derived from P. pastoris being used to hydrolytically digest high molecular weight hyaluronic acid, with optimization of digestion conditions such as pH, enzyme concentration, high molecular weight hyaluronic acid concentration, digestion temperature and digestion time, would be capable of producing a hyaluronic acid oligosaccharide mixture containing disaccharides, tetrasaccharides, hexasaccharides, octasaccharides, decasaccharides and dodecasaccharides, with respective amounts within the claimed ranges, thereby arriving at the instant invention. The process of Lv/Yuan is identical or substantially identical to the process, as described in the instant specification and claim 8, hence one of ordinary skill in the art would necessarily expect the product of Lv/Yuan, to have the structural elements, as instantly claimed. Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977).. (emphasis added, MPEP §2112.01(I)) Specifically, it has been held in In Re Best that "Where, as here, the claimed and prior art products are identical or substantially identical, or are produced by identical or substantially identical processes, the PTO can require an applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his claimed product. (See In re Ludtke, 58 CCPA 1159, 441 F.2d 660, 169 USPQ 563 (1971)). Whether the rejection is based on "inherency" under 35 USC 102, on "prima facie obviousness" under 35 USC 103, jointly or alternatively, the burden of proof is the same, and its fairness is evidenced by the PTO's inability to manufacture products or to obtain and compare prior art products. (See In re Brown, 59 CCPA 1036, 459 F.2d 531, 173 USPQ 685 (1972))…Patent Office can require applicant to prove that subject matter shown to be in prior art does not possess characteristic relied on where it has reason to believe that functional limitation asserted to be critical for establishing novelty in claimed subject matter may be inherent characteristic of prior art; this burden of proof is applicable to product and process claims reasonably considered as possessing allegedly inherent characteristics." (In re Best, Bolton, and Shaw, 195 USPQ 430 (C.C.P.A. 1977), emphasis added) Therefore, absent evidence to the contrary, the process of Lv/Yuan would necessarily produce a product with identical or substantially identical structural elements, as the product instantly claimed.
Accordingly, the instant claims are prima facie obvious over the teachings of the prior art.
Response to Arguments
Applicants’ response with respect to the rejection over Lv/Yuan, has been fully considered but is not persuasive.
Applicant argues that the goal of Ly and Yuan is production of compositions comprising tetrasaccharides and hexasaccharides of hyaluronic acid, not production of a mixture of hyaluronic acid oligosaccharides having the degree of polymerization and respective percentages, as instantly claimed. Applicants’ argument is not persuasive because a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005) While it is acknowledged that Lv and Yuan are primarily directed at producing hyaluronic acid composition comprising tetrasaccharides and hexasaccharides, it is also disclosed in Lv and Yuan that numerous variables (e.g. pH, enzyme concentration, high molecular weight hyaluronic acid concentration, digestion temperature and digestion time) can be adjusted, to manipulate the outcome of the final hyaluronic acid oligosaccharides composition. Hence, one of ordinary skill in the art considering Lv/Yuan, as a whole, would recognize that the process of Lv/Yuan could be used, with said numerous variables manipulated along a ranges of values, to produce a host of hyaluronic acid oligosaccharide compositions, within the scope of the instant claims. As it has been decided, the question in a section 103 case is not only what the references expressly teach, but what they would collectively suggest to one of ordinary skill in the art, and we are persuaded that, at least prima facie, a person of ordinary skill in the art at that time, having those two references (both of which are clearly from exactly the same art) before him, In re Antle, 58 CCPA 1382, 1387, 444 F.2d 1168, 1171, 170 USPQ 285, 287-88 (1971), would have had no difficulty in devising a process within the scope of appellant's narrower claims. In re Simon, 59 CCPA 1140, 461 F.2d 1387, 174 USPQ 114 (1972).
Applicant further argues that Lv/Yuan does not teach each and every limitation of the claimed invention, and the process of Lv/Yuna cannot be concluded to be substantially identical to that of the instant claims, because Lv/Yuan does not teach P. pastori GS115 as the expression vector. Applicants’ argument is not persuasive because P. pastori GS115 does not provide any unexpected property distinguishing the claimed invention from the prior art. P. pastori GS115 is known in the prior art, as per Zhang et al. (J. Food Biotech., 2016, IDS). Thus, one of ordinary skill could select any strain of P. pastoris to express the desired leech based hyaluronidase, including GS115 or those strains disclosed by Lv/Yuan, with a reasonable assurance of equivalent results.
Applicant further argues that the specification shows unexpected results of the claimed composition with respect to promoting and moisturizing effects, and has a more significant promoting and repairing effect on human immortalized epidermal (HaCaT) cells damaged by hydrogen peroxide, when compared to other low molecular weight (LMW) hyaluronic acid compositions. Applicants’ argument is not persuasive because the comparative experiments showing the purported superior effects, are not compared to the closest applicable prior art. The comparative experiments in the specification examine the effects of the claimed LMW hyaluronic acid composition derived from a leech based hyaluronidase, to a LMW hyaluronic acid composition derived from a bovine testis based hyaluronidase and to a LMW hyaluronic acid composition derived from a chemical synthesis. There is no comparative data showing the effects of a LMW hyaluronic acid composition derived from a leech based hyaluronidase, as produced by a method aligned with that of Lv or Yuan. Both the instant synthesis and that of Lv/Yuan use a leech based hyaluronidase and prima facie one would expect that therapeutic effects of a LMW hyaluronic acid composition derived from a leech based hyaluronidase would be similar in both instances. Hence, the data for the bovine testis hyaluronidase based composition and chemical synthesis based composition are not relevant to determine whether the instant composition shows an unexpectedly different effect than that of Lv/Yuan. Applicant is requested to note that it is well-settled that the evidence including a comparison with the closest prior art is one of elements to be considered as unexpected results (see for example, In re Merchant, 575 F.2d 865, 869, 197 USPQ 785, 788 (CCPA 1978), which is provided either in the specification or an affidavit or declaration submitted during prosecution on the issue.
The rejection is still deemed proper and is maintained.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Lv et al. (Carb. Poly., 2016, reference of record) and Yuan et al. (Carb. Poly., 2015, reference of record), in view of Qiao et al. (CN 108220364 A, 2018, reference of record).
The disclosure of Lv/Yuan is referenced as discussed above. The combined prior art does not disclose the purification conditions of claim 9.
Qiao discloses a process for purifying ultra-low molecular weight hyaluronic acid, after enzymatic hydrolysis, where the supernatant and the retentate (i.e., the remaining enzymatic hydrolyzate) filtered by the ultrafiltration system are combined, and the temperature is raised to 58° C for 30 min, add 45kg of activated carbon for 25min, then filter it with a plate and frame filter, then filter it with 0.22μm polypropylene filter. The filtrate is spray-dried, spray-dried to set the inlet air temperature to 175°C, and set the outlet air temperature to 80°C. Set the feed rate to 42L/h. (Examples 1-7)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that the purification conditions of Qiao, for purifying ultra-low molecular weight hyaluronic acid after enzymatic hydrolysis, would be directly applicable to the hyaluronic acid oligosaccharide product of Lv/Yuan. One would find this modification of Lv/Yuan obvious because Lv/Yuan and Qiao are all directed to production of ultra-low molecular weight hyaluronic acid using hyaluronidase based enzymatic hydrolysis, thus one would predict that the purification process of Qiao would be successful for Lv/Yuan.
Accordingly, the instant claims are prima facie obvious over the teachings of the prior art.
Response to Arguments
Applicant argues that the combined prior art does not render the independent claims prima facie obvious for the reasons outlined above, thus the rejection of dependent claims that reply on the teachings of said combined prior art, should be withdrawn. Applicants' arguments are not persuasive because the rejection of the independent claims is maintained as prima facie obvious over said combined prior art, as per the response to arguments above.
The rejection is still deemed proper and is maintained.
Rejections Necessitated by Amendment
The following are new ground(s) or modified rejections necessitated by Applicants' amendment, filed on 1/14/2026, wherein instant claim 7 is amended to alter the breadth and scope of the claim. Therefore, new grounds of rejection have been made.
New Grounds of Rejection
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 7 is rejected under 35 U.S.C. 112(d), as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 4 limits the expression host to be Pichia pastoris GS115, whereas claim 7 broadens the expression host to be any yeast. Thus claim 7 does not properly further limit claim 4. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new and/or modified ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to DALE R MILLER whose telephone number is (571) 272-6146. The examiner can normally be reached on M-F 7:00 AM – 3:30 PM EST.
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/DALE R MILLER/Primary Examiner, Art Unit 1693