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 .
Applicant's amendment to the claims and arguments filed on 05-02-2025 have been received and entered. Claims 2-8, 10 have been canceled. Claims 1, 9, 11 are pending.
This is a non-Final rejection.
Election/Restrictions
Applicant's election of Group I, claims 1-8, in the reply filed on 01-10-2024 is acknowledged.
Claims 9, 11 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected subject matter, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 01-10-2024.
Claim 1 is under consideration.
Priority
This instant application is a 371 of PCT/KR2019/006788 filed on 06/05/2019 that claims priority from foreign application KR 10-2018-0064752 filed on 06/05/2018. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e). Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 07-10-2025 is in compliance with the provisions of 37 CPR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Withdrawn-Claim Rejections - 35 USC § 112
Claims 1-2 were rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. In view of applicant’s cancelation of claim 2 and Applicant's amendments to base claim deleting the limitation “ wherein the animal model does not use recombinant vector” obviates the basis of the rejection. The previous rejections of claims are hereby withdrawn. Applicants' arguments with respect to the withdrawn rejections are thereby rendered moot.
Withdrawn-Claim Rejections - 35 USC § 112
Claim 1-2 were rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims. In view of applicant’s cancelation of claim 2 and Applicant's amendments to base claim 1, adding limitation “3 mg of zymosan A” obviates the basis of the rejection. The previous rejections of claims are hereby withdrawn. Applicants' arguments with respect to the withdrawn rejections are thereby rendered moot.
Withdrawn -Claim Rejections - 35 USC § 103
Claims 1, 2 were rejected under 35 U.S.C. 103 as being unpatentable over Nagayama et al (Thyroid. 2003 Mar;13(3):233-8. doi: 10.1089/105072503321582024.) in view of Lee et al (Arthritis Research & Therapy (2015) 17:218, DOI 10.1186/s13075-015-0725-z) and Banga et al (An Animal Model of Graves’ Orbitopathy. In: Chan, CC. (eds) Animal Models of Ophthalmic Diseases. Essentials in Ophthalmology. Springer, Cham. https://doi.org/10.1007/978-3-319-19434-9_8, 01 January 2015) and Taghavi et al (Taghavi et al. Journal of Inflammation (2018) 15:5, https://doi.org/10.1186/s12950-018-0182-y, Published online: 22 march 2018). Upon further consideration of the prior art of record, the obviousness rejection of record has been withdrawn in favor of the anticipation rejection provided below.
New-Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim 1 is rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Lee et al (Arthritis Research & Therapy (2015) 17:218, DOI 10.1186/s13075-015-0725-z) as evidenced by Banga et al (An Animal Model of Graves’ Orbitopathy. In: Chan, CC. (eds) Animal Models of Ophthalmic Diseases. Essentials in Ophthalmology. Springer, Cham. https://doi.org/10.1007/978-3-319-19434-9_8, 01 January 2015) and as evidenced by Taghavi et al (Taghavi et al. Journal of Inflammation (2018) 15:5, https://doi.org/10.1186/s12950-018-0182-y, Published online: 22 march 2018).
Claim interpretation:
The specification of the claimed invention teaches that the etiology of the Graves' ophthalmopathy is considered to be an autoimmune mechanism (Page 1, lines 25-26). The administration of zymosan A into the SKG mice causes increased inflammatory response and increased production of beige fat by an autoimmune reaction associated with T cells in orbital adipose tissue (Page 12, lines 28-30). Therefore, autoimmune reaction, increased inflammatory response, are interpreted as etiology of the Graves' ophthalmopathy in SKG mice with administration of zymosan A.
The specification of the claimed invention teaches that the animal model having the Graves' ophthalmopathy phenotype according to the present disclosure may be an SKG mouse in which arthritis naturally occurs due to the production of autoreactive T cells (Page 6, lines 10-12).
The specification of the claimed invention teaches that the blepharitis and exophthalmos (Graves' ophthalmopathy phenotypes) may be accompanied by an increase in the thickness of the eyelid or an increase in the thickness of the meibomian gland (Page 6, lines 3-7). Thus, blepharitis and exophthalmos and an increase in the thickness of the eyelid or an increase in the thickness of the meibomian gland are interpreted as Graves' ophthalmopathy phenotypes.
Claim 1 recites the phrase “for preparing a Graves' ophthalmopathy phenotype animal model” which is interpreted as intended use of the mouse. A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
Claim 1 recites the phrase “up to 20 weeks” which is interpreted as any time period prior to and including 20 weeks.
Regarding to claim 1, Lee et al teach that SKG mice (7–8 weeks of age) were administered with a single intraperitoneal (i.p.) injection of 3 mg of zymosan, a cell wall component prepared from Saccharomyces cerevisiae (Page 3, left column, 2nd para.) (For claim 1, the claimed: (a) intraperitoneally administering a composition comprising 3 mg of zymosan A as an active ingredient to 8-week-old SKG mice;).
Lee et al also teach maintaining the SKG mice 16 weeks postinjection (see Figure 1 and Page 4, right column, 1st para) (For claim 1, the claimed: (b) maintaining the SKG mice up to 20 weeks of age after the administration the composition)
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Regarding the limitations recited in the ‘wherein’ clauses following steps (a) and (b) of independent claim 1, it is noted that Applicant’s own disclosure and claims provide evidence that an SKG mouse of the recited age would necessarily exhibit such characteristics if treated in the manner recited in steps (a) and (b) of amended claim 1 which are taught by Lee et al method as described above. For example:
Regarding the limitation recited in the first 'wherein' clause of claim 1 that the animal model has increased beige fat around an optic nerve, the specification of the claimed invention teaches that “in an animal model having the Graves' ophthalmopathy phenotype as prepared by administering the zymosan A thereto, beige fat around the optic nerve is increased” (see the instant disclosure page 5 lines 30-31). Additionally, Banga et al teach an animal model of Grave's orbitopathy and characterize mice undergoing Grave's ophthalmopathy as exhibiting an expansion of orbital fat tissue around the optic nerve (e.g., Figure 8.1(e); etc.). This in combination with Applicant's own teachings from the instant disclosure, provide evidence that this characteristic would be inherent for an SKG mouse treated with zymosan A as recited with in instant steps (a) and (b) (For claim 1, the claimed: the animal model has increased beige fat around an optic nerve).
Regarding the limitation recited in the second 'wherein' clause of claim 1 that the Graves' ophthalmopathy phenotype exhibited by the mouse is blepharitis and exophthalmos, the specification of the claimed invention teaches that “as shown in FIG. 2, it was identified that blepharitis and exophthalmos occurred in both eyes in the SKG mouse group treated with zymosan A, compared to the control.” (see Page 9, lines 29-31). Additionally, Lee et al teaches the use of intraperitoneal injection of 3 mg of zymosan in SKG mice (Page 3, left column, 2nd para.) that lead to Periocular changes surrounding the eyeball (e.g., eyelid inflammation (blepharitis) or conjunctival discharge (indicating conjunctivitis)) were features observed coincidentally upon disease induction (Page 3, left column, 3rd para.). Also, as evidenced by Banga et al who teach that common manifestations accompanying Graves’ disease include extrathyroidal conditions of inflammatory eye disease known as Graves’ orbitopathy (GO) (also referred to as thyroid eye disease or exophthalmos) and dermopathy. The condition is characterized by expansion of the orbital fat tissue resulting principally from adipogenesis (Page 117, right column). This in combination with Applicant's own teachings from the instant disclosure, provide evidence that this characteristic would be inherent for an SKG mouse treated with zymosan A as recited with in instant steps (a) and (b) (For claim 1, the claimed: the Graves' ophthalmopathy phenotype is blepharitis and exophthalmos).
Regarding the limitation recited in the third 'wherein' clause of claim 1 that the blepharitis and exophthalmos are accompanied by an increase in a thickness of an eyelid or an increase in a thickness of a meibomian gland, the specification of the claimed invention teaches that “As identified in FIG. 3A, it was identified that the total eyelid thickness and meibomian gland thickness were significantly increased in SKG mice treated with zymosan A compared to the control” (Page 9, lines 31-33). Additionally, Lee et al teaches an obvious periocular response to zymosan that manifested initially as eyelid inflammation (i.e., swelling and redness similar to blepharitis). With zymosan, this feature was markedly enhanced and progressed to involve massive cellular infiltration in and around the meibomian glands (Fig. 2a, b), and these data suggest an autoimmune, T-cell–intrinsic component as an underlying mechanism of blepharitis and/or conjunctivitis that could be akin to prior reports of skin inflammation (Page 5, left to right column). This in combination with Applicant's own teachings from the instant disclosure, provide evidence that this characteristic would be inherent for an SKG mouse treated with zymosan A as recited with in instant steps (a) and (b) (For claim 1, the claimed: the blepharitis and exophthalmos are accompanied by an increase in a thickness of an eyelid or an increase in a thickness of a meibomian gland).
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Regarding the limitation recited in the fourth 'wherein' clause of claim 1 that the animal model of Graves' ophthalmopathy phenotype has increased expression of UCP-1 (uncoupling protein-I), leptin, adiponectin, IL-4, IL-5, IL-13, IL-2, IFN-γ and TNF-α in an orbital tissue thereof, the specification of the claimed invention teaches that “As identified in FIG. 7, when comparing SKG mice treated with zymosan A with the control, a significant increase in adipokines such as UCP-1 (uncoupling protein- I), adiponectin and leptin in the orbital tissue was identified. A significant increase in cytokines such as IL-4, IL-5 and IL-13 related to T cells could be identified together. Further, the findings of significantly increased inflammatory cytokines such as IFN-gamma, TNF-alpha and IL-2 were identified, thus suggesting that the increase in beige fat production was induced by these cytokines.” (Page 12, lines 15-21). Additionally, as evidenced by Taghavi et al who teach zymosan-induced upregulation of TLR-2, TLR-4 and TNF-α gene expression and of TNF-α release (Abstract). Zymosan significantly induced TNF-α and TLR-2 mRNA expression in both healthy (Z) animals and in melanoma bearing (ZM) animals (Page 5, right column). In addition, Taghavi et al teaches Fig. 4 : Effect of zymosan treatment (Z) on TNF-α, TLR-2 and TLR-4 genes expression in mouse. This in combination with Applicant's own teachings from the instant disclosure, provide evidence that this characteristic would be inherent for an SKG mouse treated with zymosan A as recited with in instant steps (a) and (b), and it would be expected that expression of UCP-1 (uncoupling protein-I), leptin, adiponectin, IL-4, IL-5, IL-13, IL-2, IFN-γ and TNF α are all increased in an orbital tissue since all the active steps in claim 1 are identically taught by prior art Lee et al as described above (For claim 1, the claimed: the Graves' ophthalmopathy phenotype animal model has increased expression of UCP-1 (uncoupling protein-I), leptin, adiponectin, IL-4, IL-5, IL-13, IL-2, IFN-y and TNFα in an orbital tissue thereof).
Response to Arguments
Applicant's arguments filed on 05-02-2025 have been fully considered but they are not persuasive.
1. Applicants argue that: the present invention produces unexpected and better results that could not have been anticipated even by combining the teachings of the prior art. Specifically, despite following methods similar to those described in the cited references, the resulting animal model exhibits a Graves' ophthalmopathy phenotype-particularly exophthalmos- which was neither disclosed nor suggested by the prior art. Accordingly, the invention involves more than a mere substitution of known elements and achieves a surprising technical effect (Remarks, page 5).
Exophthalmos refers to the forward protrusion of the eyeball itself, not the eyelid, and represents a fundamentally different pathological outcome. Blepharitis is typically caused by localized factors, such as meibomian gland dysfunction, bacterial infections, or dermatologic inflammation, resulting in superficial inflammation confined to the eyelid margin. In contrast, exophthalmos is caused by complex pathological processes occurring in the deep orbital tissues, including immune cell infiltration, fibrosis, and adipose tissue expansion, which lead to changes in the deep tissues of the orbit. This condition is a hallmark of Graves' ophthalmopathy. Thus, there is no direct correlation between the two conditions, nor do they induce each other. The pathogenesis, anatomical location, and underlying mechanisms of blepharitis and exophthalmos are fundamentally different (Remarks, page 6).
Response to Arguments:
It is noted that the steps of generation of animal model of Graves' ophthalmopathy phenotype of the claimed invention are identical to the method of Lee et al (same mice, same amount of zymosan A, same administration route and same amount of maintaining time). Specifically, Lee et al teach that SKG mice (7–8 weeks of age) were administered with a single intraperitoneal (i.p.) injection of 3 mg of zymosan, a cell wall component prepared from Saccharomyces cerevisiae (Page 3, left column, 2nd para.) (For claim 1, the claimed: (a) intraperitoneally administering a composition comprising 3 mg of zymosan A as an active ingredient to 8-week-old SKG mice;). Lee et al also teach that maintaining the SKG mice 16 weeks postinjection (see Figure 1 and Page 4, right column, 1st para) (For claim 1, the claimed: (b) maintaining the SKG mice up to 20 weeks of age after the administration the composition). Thus, a person of ordinary skill in the art before the effective filing date of the rejected claims would expect the resulting mice would have the same phenotypes and conditions.
As per MPEP 716.02, allegations of unexpected results: Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In the instant case, the steps of generation of animal model of Graves' ophthalmopathy phenotype of the claimed invention are identical to the teachings of Lee et al (same mice, same amount of zymosan A, same administration route and same amount of maintaining time). Thus, there is no evidence in record that the mouse model of the claimed invention would have unexpected/superior results over mouse generated by Lee et al.
As per MPEP 2112 (I), something which is old does not become patentable upon the discovery of a new property: "[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. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977).
As per MPEP 2112 (II), inherent feature need not be recognized at the relevant time: There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003) (rejecting the contention that inherent anticipation requires recognition by a person of ordinary skill in the art before the critical date and allowing expert testimony with respect to post-critical date clinical trials to show inherency); see also Toro Co. v. Deere & Co., 355 F.3d 1313, 1320, 69 USPQ2d 1584, 1590 (Fed. Cir. 2004) ("[T]he fact that a characteristic is a necessary feature or result of a prior-art embodiment (that is itself sufficiently described and enabled) is enough for inherent anticipation, even if that fact was unknown at the time of the prior invention."); Abbott Labs v. Geneva Pharms., Inc., 182 F.3d 1315, 1319, 51 USPQ2d 1307, 1310 (Fed. Cir. 1999).
2. Applicants argue that: Arthritis is not a phenotype of Graves' ophthalmopathy. The specification merely explains that the animal model of the present invention may utilize SKG mice; it does not state or imply that arthritis itself constitutes a phenotype of Graves' ophthalmopathy. SKG mice are well known as a spontaneous rheumatoid arthritis model, characterized by the development of autoimmune arthritis, not orbital disease. In contrast, the hallmark phenotype of Graves' ophthalmopathy is not arthritis but exophthalmos (protrusion of the eyeball) (Remarks, page 6), and the occurrence of exophthalmos in the present invention is distinct from the eyelid swelling and inflammation observed in Lee et al., and represents an unpredictable and surprising result (Remarks, page 6).
Response to Arguments:
It is noted that the specification of the claimed invention teaches that the animal model having the Graves' ophthalmopathy phenotype according to the present disclosure may be an SKG mouse in which arthritis naturally occurs due to the production of autoreactive T cells (Page 6, lines 10-12). Thus, Arthritis can be accompanied with SKG mouse that is used to make mouse model of Graves' ophthalmopathy.
Applicant argue that exophthalmos which is protrusion of the eyeball, and exophthalmos in the claimed invention is distinct from the eyelid swelling and inflammation observed in Lee et al. However, applicant does not provide evidence for the mice taught by Lee et al. with eyelid swelling and inflammation do not have protrusion of the eyeball. In fact, Lee et al showing Figure 2 of mice with eyelid swelling and inflammation that is showing protrusion of the eye ball (See below for Figure 2).
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3. Applicants argue that it would be unwarranted to assume or predict-without experimental validation-that such a model would accurately reproduce the pathological features of Graves' ophthalmopathy. Furthermore, although Banga et al. describe a phenotype associated with Graves' ophthalmopathy, the phenotype presented in their study is not universally observed across all animal models of the disease. The phenotypic features can vary significantly depending on the method used to generate the model. The specific features of each model vary depending on the method used to generate the mouse model. Graves' ophthalmopathy models are inherently complex, and it is essential to recognize their limitations. Although various induction models of Graves' ophthalmopathy have been reported, they differ in terms of disease incidence, progression, and pathological characteristics. Therefore, the observation of eyelid inflammation in a particular Graves' ophthalmopathy animal model does not necessarily imply that exophthalmos will also occur. It is not appropriate to generalize findings from one model to all others without specific experimental evidence (Remarks, Page 7).
Response to Arguments:
As mentioned above the steps of generation of animal model of Graves' ophthalmopathy phenotype of the claimed invention are identical to the teachings of Lee et al (same mice, same amount of zymosan A, same administration route and same amount of maintaining time). Specifically, Lee et al teach that SKG mice (7–8 weeks of age) were administered with a single intraperitoneal (i.p.) injection of 3 mg of zymosan, a cell wall component prepared from Saccharomyces cerevisiae (Page 3, left column, 2nd para.). Lee et al also teach that maintaining the SKG mice 16 weeks postinjection (see Figure 1 and Page 4, right column, 1st para). Thus, the mouse produced by the Lee et al method with identical steps as claimed invention would have the same phenotypes as mouse model of Graves' ophthalmopathy.
4. Applicants argue that: the applicant has amended claim 1 to explicitly include the step of maintaining SKG mice up to 20 weeks of age after the administration of zymosan A This step constitutes a critical element of the present invention. As shown in Figures 1 and 2 of the specification, the characteristic phenotype of Graves' ophthalmopathy was clearly observed in 20-week-old SKG mice administered with zymosan A
In contrast, Figure 2B of Lee et al. merely shows superficial ocular symptoms, such as blepharitis accompanied and conjunctival discharge, in SKG mice injected with zymosan. Notably, exophthalmos was not observed. Furthermore, Lee et al. only provide data indicating the absence of uveitis following zymosan injection at 10- and 16-weeks post-treatment, without any mention or assessment of exophthalmos. Similar findings are noted in Nagayama et al., which describes a model of Graves' hyperthyroidism but also fails to demonstrate the development of exophthalmos (Remarks, page 8).
Response to Arguments:
As describe above, the steps of generation of animal model of Graves' ophthalmopathy phenotype of the claimed invention are identical to the teachings of Lee et al (same mice, same amount of zymosan A, same administration route and same amount of maintaining time). Specifically, Lee et al teach that SKG mice (7–8 weeks of age) were administered with a single intraperitoneal (i.p.) injection of 3 mg of zymosan, a cell wall component prepared from Saccharomyces cerevisiae (Page 3, left column, 2nd para.) (For claim 1, the claimed: (a) intraperitoneally administering a composition comprising 3 mg of zymosan A as an active ingredient to 8-week-old SKG mice;). Lee et al also teach that maintaining the SKG mice 16 weeks postinjection (see Figure 1 and Page 4, right column, 1st para). Thus, it is a matter of choice for a person of ordinary skill in the art to maintain the SKG mice up to 20 weeks postinjection (e.g., 16 weeks) (For claim 1, the claimed: (b) maintaining the SKG mice up to 20 weeks of age after the administration the composition). In conclusion, a person of ordinary skill in the art before the effective filing date of the rejected claims would expect the resulting mice would have the same phenotypes and conditions such as exophthalmos.
Conclusion
No claim is allowed.
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/KHOA NHAT TRAN/Examiner, Art Unit 1632
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632