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 .1
Status of Claims
Claims 1 and 5-11 are pending and under examination. The structure of claimed ginkgolides terpene lactones, A, B, C, J and M are detailed below in Fig 1.2
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Applicant’s election without traverse of the species in the reply filed on Nov. 5, 2024 was acknowledged. With regard to the species of ginkgo terpene lactone, Applicant elected a combination of ginkgolide A, ginkgolide B, ginkgolide C and bilobalide. With regard to the species of pharmaceutical formulation, Applicant elected Embodiment 5, with active ingredients: bilobalide 960g (0.96 part); ginkgolide B 680 g (0.68 part);ginkgolide A 240 g (0.24 part); ginkgolide C 120 g (0.12 part); 1 part of glycerol monostearate, 1 part of polyethylene glycol, 1 part of carrageenan, 1 part of Arabic gum and 1 part of hydroxypropyl methyl cellulose.
Response to Attorney Arguments
Applicant's arguments filed June 9, 2026 have been fully considered but they are not persuasive. See below response to Attorney arguments.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
Claims 1 and 5-11 are rejected under 35 U.S.C. 103 as being unpatentable over Yu et al. The therapeutic potential of ginkgolide K in experimental autoimmune encephalomyelitis via peripheral immunomodulation, Int. Immunopharmacol. 70 (2019) pp. 284-294 in view of Fujioka “Experimental Autoimmune Neuritis,” Clin. Exp. Neuroimmune. 9 2018) 84-92 and Teris van Beek. Ginkgolides and bilobalide: Their physical, chromatographic and spectroscopic properties, Bioorganic & Medicinal Chemistry 13 (2005) 5001 – 5012. van Beek, Yu and Fujioka were previously cited by the Examiner.
Claim 1 is directed to a method for treating Guillain-Barre-Strohl (GBS) syndrome, comprising administering to a subject a therapeutically effective amount of ginkgo terpene lactone,
the ginkgo terpene lactone is one combination selected from bilobalide:ginkgolide B=(35-60):(40-65) w/w; or ginkgolide A:ginkgolide C=(40-75):(25-60) w/w; or ginkgolide M:ginkgolide K=(30-60):(40-70) w/w; or ginkgolide A:ginkgolide B:ginkgolide C=l:1:1 (w/w/w); or ginkgolide A:ginkgolide B:ginkgolide C:bilobalide=12:34:6:48 (w/w/w/w).
With regard to the limitation treatment and ginkgo terpene lactone limitations, Yu teaches the injection of Experimental autoimmune encephalomyelitis (EAE) model mice with the ginkgo diterpene lactone, ginkgolide K at 7.5 mg/kg that is within the claimed effective range. See Section 2.2 EAE induction and treatment, page 285, column 2.
Yu teaches EAE is a model for multiple sclerosis (MS). See page 285, column 1. Yu teaches that a MS subject’s [own] immune system perceives the myelin of a subject’s central nerve system (CNS) cells as an antigen invader, resulting in demyelination, i.e. an autoimmune response. See page 284, column 1. Yu teaches ginkgolide K inhibited the infiltration of inflammatory cells and demyelination of nerve cells in the spinal cord, and effectively ameliorated the severity of EAE in the mouse model. See abstract. Yu notes ginkgolide K therapeutic potential in EAE as a peripheral [nerve] immunomodulating agent. See page 285, column 2.
While Yu teaches the treatment of a subject with ginkgolide K in the context of treating MS with the pathophysiology of demyelination of nerve cells due to a subject’s autoimmune response to nerve myelin, Yu does not recite the particular ginkgolide combinations or the treatment of an autoimmune nerve disease, Guillain-Barré-Strohl syndrome (GBS) with ginkgo terpene lactone as claimed.
Regarding the ginkgolides claimed (A, B and C) and bilobalide, van Beek teaches the structural similarities between ginkgolides A, B, C, J, M, K and L and related compound, bilobalide, where the ginkgolides differ only by placement of either OH or H, between A, B, C, J, M, K and L, and number of OH and H groups (1, 2 and 3).
As reproduced and detailed below from van Beek Section 2.1 page 5003, column 1,, Ginkgolides A, B, C, J and M all have either H or OH at positions R1, R2 and R3, where Ginkgolide K and L disclose either OH or H, at position R (equivalent to R1 for A, B, C and J).
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Per MPEP 2144.09 (I.) the close structural similarity between the claimed ginkgolides (A, B, C, K and M) along with bilobalide, allows for a prima facie case of obviousness to be made based on the close structural similarities and similar utilities as pharmacological compounds.
While neither van Beek or Yu do not necessarily recite the various w/w percentages, the equivalence of each of the ginkgolides as substitutes for one another, a person having ordinary skill in the art would routinely optimize the amounts in the ranges recited, for example bilobalide: ginkgolide B (35-60)/(40-65) w/w or ginkgolide A:B:C (1:1:1) w/w as claimed.
With regard to treatment of Guillain-Barré-Strohl syndrome (GBS) Fujioka teaches that experimental autoimmune neuritis (EAN) is a recognized animal model for human immune-mediated neuritis, such as Guillain-Barré-Strohl syndrome (GBS) or chronic inflammatory demyelinating neuritis. See Abstract.
Fujioka teaches that experimental autoimmune neuritis (EAN) is a recognized animal model for human immune-mediated neuritis, such as Guillain-Barré-Strohl syndrome (GBS) or chronic inflammatory demyelinating neuritis. See Abstract.
Fujioka teaches EAN was introduced as an animal model of non-infectious peripheral neuropathy in conjunction with experimental allergic (autoimmune) encephalomyelitis (EAE). See page 84, column 2. Similar to the autoimmune response to myelin in EAE as taught by Yu , Fujioka teaches the subject’s autoimmune response in acute EAN, where pro-inflammatory cytokines play an important role in destroying peripheral nervous system (PNS) myelin. See page 86, column 2, middle of page.
Accordingly, a person having one of ordinary skill in the art (PHOSITA) would have found it prima facie obvious to treat GBS with the gingko terpene lactone because the prior art teaches similarity of experimental autoimmune neuritis (EAN), known as a model for the autoimmune disease GBS, to Experimental autoimmune encephalomyelitis (EAE) models for autoimmune MS and where Yu and Fujioka teach EAE is an model for an autoimmune response (such as GBS), where ginkgolide K inhibited demyelination of spinal cord never cells associated with the autoimmune response, where it is art recognized (per van Beek) the various ginkgolides claimed and bilobalide are closely structurally similar to establish the prima facie case. MPEP 2144.09(I).
It would have been prima facie obvious to substitute chemical compounds that are otherwise the same in terms of substituents on the claimed ginkgolides and similar structured compound bilobalide (van Beek), so as to treat an autoimmune disorder such as GBS with a ginkgolide (per Yu and Fujioka).
Regarding claims 5-6 and the limitations of ginkgolide A:B:C w/w; bilobalide: ginkgolide B; ginkgolide A:B:C, claimed, as detailed above, while neither van Beek or Yu do not necessarily recite the various w/w percentages, the equivalence of each of the ginkgolides as substitutes for one another, a PHOSITA would routinely optimize the amounts in the ranges recited, for example bilobalide: ginkgolide B (35-60)/(40-65) w/w or ginkgolide A:B:C (1:1:1) w/w as claimed.
With regard to claim 7, because Yu teaches the treatment of Guillain-Barre Strohl syndrome (GBS) in a subject, it would be prima facie obvious for one of ordinary skill in the to treat subtypes of GBS as claimed.
Regarding claims 8-9, as detailed above, the claimed combinations and amounts, as detailed above, while neither van Beek or Yu do not necessarily recite the various w/w percentages, the equivalence of each of the ginkgolides as substitutes for one another, a person having ordinary skill in the art would routinely optimize the amounts in the ranges recited, for example bilobalide: ginkgolide B (35-60)/(40-65) w/w or ginkgolide A:B:C (1:1:1) w/w as claimed. With regard to claims 8-9 requiring a carrier that comprises one or more of various excipients such as a wetting agent that comprises one or more selected from water and alcohol, van Beek teaches the solubility of the various ginkgolides in water and alcohol, such as methanol-water. See Section 2.4, page 5003, column 2.
Claim 10 defines a therapeutically effect amount range is 4.5-15mg/kg. Yu teaches the injection of ginkgolide K at 7.5 mg/kg that is within the claimed range. See Section 2.2 EAE induction and treatment, page 285, column 2.
Regarding claim 11 and a dose of 160 mg/day for 30 days, based on the teachings of Yu and administration of 7.5 mg/kg of a subject, and based on the weight of an intended subject and clinical response to the claimed therapeutically effective amount of a subject in response to treatment, it would be routine to optimize the art to predictably arrive at the dose of claim 11. For example, see Yu at Figure 7 at page 292, where ginkgolide K (GK) elicited differing immune responses at different GK dose concentrations as well as compared to a DMSO control, along with teaching of 7.5mg/kg dose. See MPEP 2144.05 (II.) Routine Optimization.
RESPONSE TO ATTORNEY ARGUMENTS:
The Attorney response states the claimed particular ginkgolide combinations for the treatment of Guillain Barre-Strohl syndrome (GBS) achieves synergistic effects compared with using each ginkgolide alone Ginkgolide A, B, C, K, M (GA, GB, GC, GK and GM) or bilobalide (BB).
The Attorney response states there should not be reasonable expectation of success of achieving such synergistic effects.
The Attorney response states:
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The Attorney response states per Table 5, synergistic effects are achieved by administering the combination of BB:GB B=(35-60):(40-65) w/w.
Similarly, the Attorney response states:
(groups I, II and III) ginkgolide A: ginkgolide C=(40-75):(25-60) w/w, synergistic effects correspond to doses administered at 6.0, 8.0 and 9.0 mg/kg (see Table 3);
(groups IV, V and VI)ginkgolide M: ginkgolide K=(30-60):(40-70) w/w, synergistic effects correspond to doses administered at 6.4, 7.5 and 9.0 mg/kg (see Table 4);
(group X)ginkgolide A: ginkgolide B: ginkgolide C=1 1: 1 (w/w/w), synergistic effects correspond to a dose administered at 13.5 mg/kg ONLY (see Table 5);
(group XI)ginkgolide A: ginkgolide B: ginkgolide C:bilobalide=12:34:6:48 (w/w/w/w), synergistic effects correspond to a dose of 9.4 mg/kg ONLY (see Table 5).
The Attorney response states there are considerable differences in biological activity between Ginkgo extracts and individual Ginkgo terpene Trilactones. See references to Van Beek and Yu.
In response to the unexpected results, while the arguments are not provided via a Rule 132 Declaration, the requirements of MPEP 716.02 providing guidance with regard to Affidavits or Declarations under 37 CFR 1.132 are applicable here.
MPEP 716.02(d) requires that unexpected results must be commensurate in scope with the claimed invention.
Claim 1 recites the various w/w of bilobalide and Ginkgolide A, B, C, M and K are spelled out. However, limitations of doses (therapeutically effective amounts) administered to a subject are not recited claim 1. Further, claim 1 does not recite a route of administration. Claims 8-9 broadly recite a medicament with numerous excipients, without explanation of the particular route of administration.
Not until claims 10-11 are the claimed therapeutically effective amounts claimed, where it is broadly recited as 4.5-15 mg/kg applicable to any of the combinations of claim 1.
The synergistic effects emphasized by the Attorney response rely upon Tables 3-5 of the specification. Tables 3-5 are supported by the specification’s Test example 1 starting at page 5 of the specification. Test Example 1 relies upon a specific formulation of the Ginkgolide groups/combinations A-K and I-XI and bilobalide group recited therein at pages 6-7. The formulations of Tables 3-5 are limited specifically to a (glycerin: ethanol=6:4 W/W) to reach 5 mg/ml, and which were configured to reach corresponding concentrations by using sterilized drinking water for Intragastric administration ONLY. See page 7, lines 23-25. The single formulation of Test Example 1 tied to the synergistic results of Table 5, etc., is far narrower than the scope of the rejected claims and therefore cannot support unexpected results to overcome the prima facie case of obviousness.
Further, the unexpected results of synergism (per Table 5 etc.), only occur at specific doses (therapeutically effective amounts and NOT the full range of therapeutically effective amounts of 4.5-15 mg/kg or 160 mg/day for 30 days per claims 10-11.
Ginkgolide groups VII, VIII and IX only support synergistic unexpected results at therapeutically effective amounts of 7.5, 6.9 and 9 mg/kg. See above.
Ginkgolide groups I, II and III only support synergistic unexpected results at therapeutically effective amounts of 8.0, 6.0 and 9 mg/kg. See above.
Ginkgolide groups IV, V and VI only support synergistic unexpected results at therapeutically effective amounts of 8.0, 6.0 and 9 mg/kg. See above.
Ginkgolide group X only supports synergistic unexpected results at a therapeutically effective amount of 13.5 mg/kg. See above.
Ginkgolide group XI only supports synergistic unexpected results at a therapeutically effective amount of 9.4 mg/kg. See above
Therefore, Attorney arguments relying upon unexpected synergistic results cannot overcome the prima face case as they are not commensurate in scope with the claimed method.
The Attorney response states ginkgolides A, B, C, M and K do not have similar effects although they have structural similarities. See Section 1 of response reference to Feng, Ban Beek and Hu.
The Attorney response states ginkgolides A, B, C, M and K do not have similar effects. See to Evidence 2 section of response and reference to Hu.
The Attorney response states contrary to the Examiner’s rejection, Yu does not teach GK can act as a neuromodulator in context of peripheral immunity, the peripheral nervous system, where it is argued diseases of nervous system and immune system have no hierarchical relationship.
The Attorney response states Yu teaches experiments of the spleen vs. the peripheral immune system.
The Attorney response states Yu is directed to the treatment of multiple sclerosis (MS), versus claimed Guillain Barre Strohl syndrome (GBS), where FDA approved MS treatments are not approved to treat GBS (citing to WHO website, Merck Manual and Richard et al. LANCET article, as per Evidence sections 2 and 3 of the response).
In response, while the Attorney response evidences differences between GBS and MS in terms of approved treatments (for example corticosteroids as per Richard), it is noted that the art teaches suitability of treatments for both MS and GBS. See for example claims 1-5 of EP 3243509A1 teaching a pharmaceutical composition comprising Ginkgo biloba extract to treat degenerative and peripheral nervous system (NS) diseases, including MS and GBS.
Conclusion and Correspondence
In conclusion, no claims are allowed. THIS ACTION IS MADE FINAL. 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 nonprovisional extension fee (37 CFR 1.17(a)) 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to WILLIAM LEE whose telephone number is (571)270-3876. The examiner can normally be reached M-F.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam C. Milligan can be reached at (571) 270-7674. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/WILLIAM Y LEE/Examiner, Art Unit 1623
/GEORGE W KOSTURKO/Primary Examiner, Art Unit 1621
1 This application claims earliest foreign priority from CHINA 201910286519.3 filed on April 10 2019.
2 Zeng et al. Biosynthesis pathways of ginkgolides Pharmacognosy Reviews Jan-Jun 2013 Vol 7 Issue 13
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