Page 1

Judgment Pronouncement Date: February 13, Reiwa 7 (2025) 

Case Numbers: Reiwa 5 (Administrative Lawsuit) No. 10093 (Case 1), No. 10094 (Case 2) 

Request for Cancellation of Judgment

Date of Conclusion of Oral Arguments: December 2, Reiwa 6 (2024) 

Judgment 

- Plaintiff in Case 1 (Participant in Invalidation Trial): Towa Reproduction Co., Ltd. 

- Litigation Representative (Attorney): [Name not fully provided] 

- Plaintiffs in Case 2 (Claimants): [Multiple plaintiffs listed, but names not fully provided due to repetition and OCR limitations] 

(Note: The rest of the page contains repetitive or incomplete text, likely due to OCR errors, and does not provide additional substantive content.)

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(Note: This page contains mostly repetitive "同" (same) and "1" characters, suggesting an OCR artifact or placeholder. The only meaningful content is:) 

- Litigation Representative (Attorney): [Name not fully provided] 

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Timeline and Related Events: 

1. March 30, Reiwa 3 (2021): Permission to participate was granted. 

2. March 3, Reiwa 4 (2022): The defendant filed a request to amend the scope of the patent claims for the patent in question. 

3. July 12, Reiwa 5 (2023): The Patent Office approved the amendment request mentioned above and notified the plaintiffs in Case 1 on the 1st day [date incomplete]. 

4. August 18, Reiwa 5 (2023): The plaintiffs filed lawsuits (Case 1 and Case 2) to seek cancellation of the judgment in question. 

Related Invalidation Trial and Its Outcome: 

- March 31, Reiwa 2 (2020): The plaintiff in Case 1 requested an invalidation trial against Patent No. [number incomplete, likely "5"]. 

- October 27, Reiwa 3 (2021): The Patent Office conducted the trial under Invalidation Case No. 2020-800034, approved the defendant’s requested amendment to the scope of claims, and ruled that the invalidation request was unfounded. 

(Note: The remainder of the page contains numbered lines without substantive content, likely an OCR artifact.)

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 Page 4

Patent Claim in Question: 

A pharmaceutical agent containing (E)-8-(3,4-dimethoxystyryl)-1,3-diethyl-7-methylxanthine, characterized by: 

- The agent is intended for human patients with Parkinson’s disease who, during L-DOPA therapy, have reached a stage exhibiting wearing-off phenomena and/or on-off fluctuations. 

- The agent is administered to said patients to reduce the off-time associated with on-off fluctuations. 

Specification and Drawings (Excerpt): 

The specification of the patent in question (attached as Appendix 2) includes the following disclosures: 

1. The invention relates to a method for treating patients with motor disorders by administering at least one adenosine A2A receptor antagonist ([0001]). 

2. No cure is known for Parkinson’s disease. Most early-stage Parkinson’s patients respond well to symptomatic treatment with dopamine replacement therapy, but disability increases as the disease progresses ([0005]). 

(Note: The rest of the page repeats "25" excessively, likely an OCR error, and lacks additional substantive content.)

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 Page 5

[0007], [0009]: 

- Behavioral studies indicate that several adenosine A2A receptor antagonists improve motor dysfunction in animal models of Parkinson’s disease (e.g., monkeys treated with MPTP, a neurotoxin), while also exhibiting characteristics distinct from dopaminergic drugs. 

- Studies on the anti-Parkinson’s effects of KW-6002, a selective adenosine A2A receptor antagonist, using MPTP-treated marmosets and cynomolgus monkeys, show that adenosine A2A antagonists can… [text truncated]. 

(Note: The truncation and subsequent "数uum" repetitions suggest an OCR issue. The content likely continues into the specification details.)

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 Page 51 (Appendix 1: List of Abbreviations)

- This Patent: Patent No. 4376630, with the defendant as the patent holder. 

- Priority Date: January 28, Heisei 14 (2002), with the priority claim country being the United States. 

- Judgment in Question: Judgment made on July 12, Reiwa 5 (2023) regarding Invalidation Case No. 2020-800076 (Claimants: Plaintiffs in Case 2; Participant: Plaintiff in Case 1), which is the subject of this lawsuit. 

- Invention in Question: The invention covered by this patent. 

- Specification in Question: The specification associated with this patent. 

- Exhibit 3 Invention: The invention described in Exhibit 3 (NEUROLOGY, 1999, Vol. 52, p. 1916), as recognized by the judgment in question (see Section 2, 3(2)). 

- KW-6002: (E)-8-(3,4-dimethoxystyryl)-1,3-diethyl-7-methylxanthine. 

- L-DOPA: A dopamine precursor converted to dopamine by L-DOPA decarboxylase, also referred to as Levodopa or L-DOPA in some contexts (standardized here as "L-DOPA" unless directly quoting sources). 

- Adenosine A2A Receptor: One of the four main subtypes on which adenosine acts (standardized as "Adenosine A2A Receptor" unless quoting sources). 

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 Page 52 (Appendix 2: Specification Details and Drawings Excerpt)

[Technical Field] 

[0001] 

This invention relates to a method for treating patients with motor disorders characterized by the administration of at least one adenosine A2A receptor antagonist. 

[Background Art] 

[0005] 

Typically, the initial symptoms of Parkinson’s disease include limb tremors (shaking or vibration), particularly when the body is at rest. Tremors often begin unilaterally, frequently occurring in one hand. Other common symptoms include slow movement (bradykinesia), inability to move (akinesia), limb rigidity, shuffling gait, stooped posture, and other motor impairments. Patients with Parkinson’s disease often lose facial expressiveness and speak in a quiet voice. The condition may cause secondary symptoms such as depression, anxiety, personality changes, cognitive impairment, sleep disorders, visual disturbances, or sexual dysfunction. Therapy primarily focuses on controlling the imbalance between neurotransmitters to manage these symptoms. Most early-stage Parkinson’s patients respond well to symptomatic dopamine replacement therapy, but disability increases as the disease progresses. 

[0007] 

Most Parkinson’s disease symptoms arise from dopamine deficiency, and most anti-Parkinson’s drugs aim to restore dopamine levels or mimic its effects. However, these drugs do not permanently restore dopamine nor precisely replicate its actions. While the primary feature of Parkinson’s disease is the loss of dopamine-producing cells in the substantia nigra, non-dopaminergic nerve cells are also lost. Furthermore, dopamine-responsive cells exist not only in the substantia nigra but also in other brain regions. Consequently, drugs effective for Parkinson’s disease may inhibit these cells, potentially causing side effects such as clicks, hallucinations, or confusion. 

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[Continued from 0007]: 

L-DOPA was reported in 1967 and has since been the most effective anti-Parkinson’s drug… [text trails off into repetitive OCR errors]. 

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 Page 54

[0033] 

Behavioral studies demonstrate that adenosine A2A receptor antagonists exhibit unique characteristics distinct from dopaminergic drugs while improving motor function… 

The anti-Parkinson’s effects of KW-6002, a selective adenosine A2A receptor antagonist, have been studied using MPTP-treated marmosets and cynomolgus monkeys. In MPTP-treated marmosets, oral administration of KW-6002 induced a dose-dependent increase in spontaneous movement, lasting up to 1 hour. Spontaneous movement increased to levels observed in normal animals, whereas L-DOPA induced hyperactivity. Additionally, in MPTP-treated marmosets pre-treated with L-DOPA, 21 days of KW-6002 treatment induced little to no dyskinesia, whereas L-DOPA under the same conditions caused significant dyskinesia. When KW-6002 (20 mg/kg) was administered with low-dose L-DOPA daily for 5 days in MPTP-treated marmosets conditioned to develop dyskinesia, anti-Parkinson’s activity increased without exacerbating dyskinesia. Collectively, these findings suggest that adenosine A2A antagonists may provide anti-Parkinson’s effects as a standalone therapy for early-stage patients and improve anti-Parkinson’s effects without increasing dyskinesia in patients with motor complications from L-DOPA therapy. 

[0034] 

The mechanism by which adenosine A2A antagonists exert anti-Parkinson’s effects remains incompletely understood, but the following mechanism has been proposed… [continues]. 

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 Page 55

[0038] 

The A2A receptor-mediated mechanism involves medium spiny neurons in the striatopallidal system… 

Adenosine A2A receptor antagonists are provided as a means to treat Parkinson’s disease with little to no risk of exacerbating or inducing motor complications, a common side effect of typical dopaminergic drugs… 

[Disclosure of the Invention] 

[Means for Solving the Problem] 

[0039] 

This invention provides a method for reducing or suppressing the side effects of L-DOPA therapy by administering or co-administering one or more A2A receptor antagonists. Such treatment may be effective in treating patients with motor complications induced by L-DOPA or other dopaminergic drugs, reducing off-time and/or improving dyskinesia. 

[0121] 

A preferred adenosine A2A receptor antagonist useful in the method of this invention includes (E)-8-(3,4-dimethoxystyryl)-1,3-diethyl-7-methylxanthine (Formula II). 

[0122] 

[Chemical Formula 121: Structure of KW-6002 provided as an SVG image, not reproduced here.] 

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 Page 56

[0123] 

In this invention, Formula II is referred to as KW-6002. 

“Reducing or suppressing side effects of L-DOPA” is understood to mean, according to this invention, that the compound reduces the amount of “off” state during a patient’s awake time. The “off” state, as per this invention, refers to the period when the therapeutic effects of Parkinson’s disease medication wear off, resulting in symptoms classified by scales such as the Unified Parkinson’s Disease Rating Scale (UPDRS) and Hoehn and Yahr (HY) scale. 

[0124] 

The invention also aims to reduce L-DOPA side effects by increasing the proportion of “on” state during a patient’s awake time. The “on” state refers to the period after taking Parkinson’s medication when symptoms classified by UPDRS and HY scales are relatively absent. Patients treatable by this method include those with early, intermediate, and advanced stages of Parkinson’s disease, with or without motor complications as assessed by the Parkinson’s Dyskinesia Scale (PDS). 

[Example 1] 

[0147] 

The safety and efficacy of KW-6002, an adenosine A2A receptor antagonist, as a treatment for Parkinson’s disease worsened by L-DOPA-related motor complications were evaluated in a 12-week multicenter exploratory study. PD subjects with motor complications were randomly assigned to one of three parallel treatment arms: placebo (n=29), KW-6002 up to 20 mg/day (n=26), or KW-6002 up to 40 mg/day (n=28). Two primary efficacy endpoints were established: 1) change in “off” time assessed by investigators during an 8-hour visit, and 2) change in “off” time assessed by subjects’ home motor diaries. 

[0148] 

[Continued on Page 57.] 

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 Page 57

Of the 83 enrolled subjects, 65 completed the trial; dropout rates were similar across treatment groups. KW-6002 treatment was significantly more effective than placebo in reducing the proportion of awake time spent in the “off” state. When assessed by home diaries, the proportion of awake time in the “off” state increased by 2.2% in the placebo group, while it decreased by 7.1% in the KW-6002 group (p=0.008). Off-time reduction was 1.7 hours greater in the KW-6002 group compared to placebo (p=0.004). The 8-hour on/off assessment by investigators reached statistical significance (p=0.054), with KW-6002-treated patients spending 0.51 fewer hours in the “off” state compared to placebo (p=0.061). 

The trial also showed a reduction in early dystonia from baseline to week 12 in KW-6002-treated patients compared to placebo. 

[0149] Method 

This was a 12-week, double-blind, placebo-controlled, randomized, parallel-group multicenter study evaluating the safety and efficacy of KW-6002 as an adjunctive therapy in PD patients with motor complications treated with L-DOPA. Eligible patients met the United Kingdom Parkinson’s Disease Society (UKPDS) Brain Bank diagnostic criteria (Daniel et al., 1993), had been using L-DOPA/carbidopa for at least one year, took it at least four times daily, and exhibited motor complications such as end-of-dose wearing-off… 

[0151] 

Subjects who successfully completed screening and baseline assessments were randomly assigned in a 1:1:1 ratio to one of two KW-6002 dosage groups or a corresponding placebo. Patients assigned to KW-6002 received 5 mg/day during weeks 1-4, 10 mg/day during weeks 5-8, and 20 mg/day during weeks 9-12 (5/10/20 group), or… 

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 Page 58

[Continued from 0151]: 

10 mg/day during weeks 1-4, 20 mg/day during weeks 5-8, and 40 mg/day during weeks 9-12 (10/20/40 group), taken once daily with breakfast… 

[0152] Results 

A total of 83 subjects were randomized. Subjects in all three treatment groups adhered to their trial medication at a 99% rate based on pill count. No significant changes in the average daily L-DOPA dose were observed in any treatment group or when comparing the combined KW-6002 groups to placebo during the trial. 

[0153] 

When assessed by home diaries, subjects assigned to the two KW-6002 groups showed a significant reduction in off-time compared to the placebo group (Figure 1). The proportion of awake time spent in the “off” state increased by 2.2% in the placebo group, while it decreased by 7.1% in the KW-6002 group (p=0.008). Both KW-6002 dosage groups individually, as well as the combined KW-6002 group, showed a significant reduction in the proportion of off-time compared to placebo. Similarly, the total off-time decreased significantly in the combined KW-6002 group, with a 1.2-hour reduction compared to a 0.5-hour increase in the placebo group (p=0.004) (Figure 1). 

[0154] 

The combined KW-6002 group showed a greater trend toward reduced off-time compared to placebo, as confirmed by the physician’s off-time assessment during an 8-hour clinic visit. Off-time decreased by 3.3% in the placebo group, compared to 10.0% in the KW-6002 group (p=0.05). Similarly, off-time decreased by 0.3 hours in the placebo group, compared to 0.8 hours in the KW-6002 group… 

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 Page 59

[Continued from 0154]: 

(p=0.06). The reduction in off-time in the high-dose KW-6002 group (10/20/40 group) was significant (p=0.02). 

Early dystonia in KW-6002-treated patients decreased from baseline to week 12 compared to placebo. 

[0155] 

KW-6002 demonstrated excellent safety and tolerability… 

Based on the trial results, the adenosine A2A receptor antagonist KW-6002 can safely and effectively reduce off-time in Parkinson’s disease patients with motor complications caused by L-DOPA. 

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 Notes on Translation

- Dates: Japanese dates use the Reiwa era (e.g., Reiwa 7 = 2025). These have been converted to the Gregorian calendar for clarity. 

- OCR Errors: The original text contains numerous OCR artifacts (e.g., repetitive "同," "1," or "数uum"). I’ve omitted these where they do not contribute meaning and focused on substantive content. 

- Technical Terms: Patent-specific terms (e.g., "wearing-off," "on-off fluctuations") are retained in their standard English forms as used in medical and patent contexts. 

- Truncation: Some sections were incomplete due to the provided text ending abruptly. I’ve indicated where this occurs. 

Let me know if you need further clarification or additional sections translated!